Academic Appointments

Administrative Appointments

  • Director, Clinical Genomics Laboratory (2020 - Present)

Honors & Awards

  • William K. Bowes Jr Award in Medical Genetics, Partners HealthCare Center for Personalized Genetic Medicine, Harvard Medical School (2011)
  • Dr. Harold and Golden Lamport Research Award, Icahn School of Medicine at Mount Sinai (2012)

Boards, Advisory Committees, Professional Organizations

  • Steering Committee, Pharmacogene Variation Consortium (PharmVar) (2016 - Present)
  • Member, Association for Molecular Pathology (AMP) Pharmacogenomics (AMP PGx) Working Group (2016 - Present)
  • Steering Committee, Clinical Pharmacogenetics Implementation Consortium (CPIC) (2019 - Present)
  • Scientific Editor, Medical Genetics Summaries (MGS); NCBI/NIH, National Library of Medicine (NLM) (2019 - Present)

Professional Education

  • Ph.D., University of Saskatchewan, Saskatoon, SK, Canada, Department of Pathology (2005)
  • Fellowship, Icahn School of Medicine at Mount Sinai, New York, NY, Clinical Molecular Genetics and Genomics (2005)
  • Board Certification, American Board of Medical Genetics and Genomics (ABMGG), Clinical Molecular Genetics and Genomics (2007)
  • Fellowship, Icahn School of Medicine at Mount Sinai, New York, NY, Clinical Cytogenetics and Genomics (2007)
  • Board Certification, American Board of Medical Genetics and Genomics (ABMGG), Clinical Cytogenetics and Genomics (2009)
  • M.S., Icahn School of Medicine at Mount Sinai, New York, NY, Clinical Research Training Program (CRTP) (2016)

All Publications

  • Effects of Testing and Disclosing Ancestry-Specific Genetic Risk for Kidney Failure on Patients and Health Care Professionals: A Randomized Clinical Trial. JAMA network open Nadkarni, G. N., Fei, K., Ramos, M. A., Hauser, D., Bagiella, E., Ellis, S. B., Sanderson, S., Scott, S. A., Sabin, T., Madden, E., Cooper, R., Pollak, M., Calman, N., Bottinger, E. P., Horowitz, C. R. 2022; 5 (3): e221048


    Importance: Risk variants in the apolipoprotein L1 (APOL1 [OMIM 603743]) gene on chromosome 22 are common in individuals of West African ancestry and confer increased risk of kidney failure for people with African ancestry and hypertension. Whether disclosing APOL1 genetic testing results to patients of African ancestry and their clinicians affects blood pressure, kidney disease screening, or patient behaviors is unknown.Objective: To determine the effects of testing and disclosing APOL1 genetic results to patients of African ancestry with hypertension and their clinicians.Design, Setting, and Participants: This pragmatic randomized clinical trial randomly assigned 2050 adults of African ancestry with hypertension and without existing chronic kidney disease in 2 US health care systems from November 1, 2014, through November 28, 2016; the final date of follow-up was January 16, 2018. Patients were randomly assigned to undergo immediate (intervention) or delayed (waiting list control group) APOL1 testing in a 7:1 ratio. Statistical analysis was performed from May 1, 2018, to July 31, 2020.Interventions: Patients randomly assigned to the intervention group received APOL1 genetic testing results from trained staff; their clinicians received results through clinical decision support in electronic health records. Waiting list control patients received the results after their 12-month follow-up visit.Main Outcomes and Measures: Coprimary outcomes were the change in 3-month systolic blood pressure and 12-month urine kidney disease screening comparing intervention patients with high-risk APOL1 genotypes and those with low-risk APOL1 genotypes. Secondary outcomes compared these outcomes between intervention group patients with high-risk APOL1 genotypes and controls. Exploratory analyses included psychobehavioral factors.Results: Among 2050 randomly assigned patients (1360 women [66%]; mean [SD] age, 53 [10] years), the baseline mean (SD) systolic blood pressure was significantly higher in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes and controls (137 [21] vs 134 [19] vs 133 [19] mm Hg; P=.003 for high-risk vs low-risk APOL1 genotypes; P=.001 for high-risk APOL1 genotypes vs controls). At 3 months, the mean (SD) change in systolic blood pressure was significantly greater in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes (6 [18] vs 3 [18] mm Hg; P=.004) and controls (6 [18] vs 3 [19] mm Hg; P=.01). At 12 months, there was a 12% increase in urine kidney disease testing among patients with high-risk APOL1 genotypes (from 39 of 234 [17%] to 68 of 234 [29%]) vs a 6% increase among those with low-risk APOL1 genotypes (from 278 of 1561 [18%] to 377 of 1561 [24%]; P=.10) and a 7% increase among controls (from 33 of 255 [13%] to 50 of 255 [20%]; P=.01). In response to testing, patients with high-risk APOL1 genotypes reported more changes in lifestyle (a subjective measure that included better dietary and exercise habits; 129 of 218 [59%] vs 547 of 1468 [37%]; P<.001) and increased blood pressure medication use (21 of 218 [10%] vs 68 of 1468 [5%]; P=.005) vs those with low-risk APOL1 genotypes; 1631 of 1686 (97%) declared they would get tested again.Conclusions and Relevance: In this randomized clinical trial, disclosing APOL1 genetic testing results to patients of African ancestry with hypertension and their clinicians was associated with a greater reduction in systolic blood pressure, increased kidney disease screening, and positive self-reported behavior changes in those with high-risk genotypes.Trial Registration: Identifier: NCT02234063.

    View details for DOI 10.1001/jamanetworkopen.2022.1048

    View details for PubMedID 35244702

  • Clinical pharmacogenomic testing and reporting: A technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics Tayeh, M. K., Gaedigk, A., Goetz, M. P., Klein, T. E., Lyon, E., McMillin, G. A., Rentas, S., Shinawi, M., Pratt, V. M., Scott, S. A., ACMG Laboratory Quality Assurance Committee. Electronic address:,, 2022


    Pharmacogenomic testing interrogates germline sequence variants implicated in interindividual drug response variability to infer a drug response phenotype and to guide medication management for certain drugs. Specifically, discrete aspects of pharmacokinetics, such as drug metabolism, and pharmacodynamics, as well as drug sensitivity, can be predicted by genes that code for proteins involved in these pathways. Pharmacogenomics is unique and differs from inherited disease genetics because the drug response phenotype can be drug-dependent and is often unrecognized until an unexpected drug reaction occurs or a patient fails to respond to a medication. Genes and variants with sufficiently high levels of evidence and consensus may be included in a clinical pharmacogenomic test; however, result interpretation and phenotype prediction can be challenging for some genes and medications. This document provides a resource for laboratories to develop and implement clinical pharmacogenomic testing by summarizing publicly available resources and detailing best practices for pharmacogenomic nomenclature, testing, result interpretation, and reporting.

    View details for DOI 10.1016/j.gim.2021.12.009

    View details for PubMedID 35177334

  • Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clinical pharmacology and therapeutics Lee, C. R., Luzum, J. A., Sangkuhl, K., Gammal, R. S., Sabatine, M. S., Stein, C. M., Kisor, D. F., Limdi, N. A., Lee, Y. M., Scott, S. A., Hulot, J. S., Roden, D. M., Gaedigk, A., Caudle, K. E., Klein, T. E., Johnson, J. A., Shuldiner, A. R. 2022


    CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at

    View details for DOI 10.1002/cpt.2526

    View details for PubMedID 35034351

  • Pharmacogenomic polygenic risk score for clopidogrel responsiveness among Caribbean Hispanics: A candidate gene approach. Clinical and translational science Duconge, J., Santiago, E., Hernandez-Suarez, D. F., Monero, M., Lopez-Reyes, A., Rosario, M., Renta, J. Y., Gonzalez, P., Ileana Fernandez-Morales, L., Antonio Velez-Figueroa, L., Arce, O., Marin-Maldonado, F., Nunez, H., Melin, K., Scott, S. A., Ruano, G. 2021


    This multicenter clinical study was aimed at conducting a targeted pharmacogenomic association analysis of residual on-clopidogrel platelet reactivity in 474 Caribbean Hispanic patients. Platelet reactivity was measured using the VerifyNow P2Y12 assay and clopidogrel resistance was defined as P2Y12 reaction units (PRUs) greater than or equal to 208. Genotyping was performed using the whole-genome Infinium MEGA BeadChip array. An ancestry-adjusted, weighted polygenic risk score (wPGxRS) was developed to account for the effect of multiple variants on PRU and compared between clopidogrel responders and nonresponders. The mean PRU across the study cohort was 173.8±68.5 and 33.5% of patients were defined as clopidogrel resistant. Multivariate linear regression showed that 19% of PRU variability was attributed to nine independent predictors, with CYP2C19*2 (rs4244285) accounting for ~7% of observed PRU variation (p<0.001). PON1 rs662, ABCB1/MDR1 rs2032582, PEAR1 rs12041331 carrier status, and the interaction between African ancestry and rs12041331 carriers also predicted PRU among the participants (p≤0.05). A clear gene-dose effect was detected between PRU and CYP2C19*2 genotype, consistent with previous studies in European patient populations, as well as rs12777823. Importantly, a significant positive correlation was detected between our novel wPGxRS (4 variants) and PRU among the Hispanic patient population (rp =0.35, p<0.001). Moreover, the wPGxRS discriminated between nonresponders and responders (p=0.003), indicating that this multigene-based score is a useful predictor of clopidogrel resistance among Caribbean Hispanics. Taken together, these results help close the gap of knowledge on clopidogrel pharmacogenomics and its potential clinical implementation in this under-represented population.

    View details for DOI 10.1111/cts.13124

    View details for PubMedID 34415683

  • PharmVar GeneFocus: CYP2C9. Clinical pharmacology and therapeutics Sangkuhl, K., Claudio-Campos, K., Cavallari, L. H., Agundez, J., Whirl-Carrillo, M., Duconge, J., Del Tredici, A. L., Wadelius, M., Botton, M. R., Woodahl, E. L., Scott, S. A., Klein, T. E., Pratt, V. M., Daly, A. K., Gaedigk, A. 2021


    The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene.Genetic variation within the CYP2C9 gene locusimpacts the metabolism or bioactivation of many clinically important drugs including NSAIDs, phenytoin, anti-diabetic agents and angiotensin receptor blocker. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

    View details for DOI 10.1002/cpt.2333

    View details for PubMedID 34109627

  • Deletion of ERF and CIC causes abnormal skull morphology and global developmental delay. Cold Spring Harbor molecular case studies Singh, R., Cohen, A. S., Poulton, C., Hjortshoj, T. D., Akahira-Azuma, M., Mendiratta, G., Khan, W. A., Azmanov, D. N., Woodward, K. J., Kirchhoff, M., Shi, L., Edelmann, L., Baynam, G., Scott, S. A., Jabs, E. W. 2021; 7 (3)


    The ETS2 repressor factor (ERF) is a transcription factor in the RAS-MEK-ERK signal transduction cascade that regulates cell proliferation and differentiation, and pathogenic sequence variants in the ERF gene cause variable craniosynostosis inherited in an autosomal dominant pattern. The reported ERF variants are largely loss-of-function, implying haploinsufficiency as a primary disease mechanism; however, ERF gene deletions have not been reported previously. Here we describe three probands with macrocephaly, craniofacial dysmorphology, and global developmental delay. Clinical genetic testing for fragile X and other relevant sequencing panels were negative; however, chromosomal microarray identified heterozygous deletions (63.7-583.2 kb) on Chromosome 19q13.2 in each proband that together included five genes associated with Mendelian diseases (ATP1A3, ERF, CIC, MEGF8, and LIPE). Parental testing indicated that the aberrations were apparently de novo in two of the probands and were inherited in the one proband with the smallest deletion. Deletion of ERF is consistent with the reported loss-of-function ERF variants, prompting clinical copy-number-variant classifications of likely pathogenic. Moreover, the recent characterization of heterozygous loss-of-function CIC sequence variants as a cause of intellectual disability and neurodevelopmental disorders inherited in an autosomal dominant pattern is also consistent with the developmental delays and intellectual disabilities identified among the two probands with CIC deletions. Taken together, this case series adds to the previously reported patients with ERF and/or CIC sequence variants and supports haploinsufficiency of both genes as a mechanism for a variable syndromic cranial phenotype with developmental delays and intellectual disability inherited in an autosomal dominant pattern.

    View details for DOI 10.1101/mcs.a005991

    View details for PubMedID 34117072

  • Multi-Institutional Implementation of Clinical Decision Support for APOL1, NAT2, and YEATS4 Genotyping in Antihypertensive Management. Journal of personalized medicine Schneider, T. M., Eadon, M. T., Cooper-DeHoff, R. M., Cavanaugh, K. L., Nguyen, K. A., Arwood, M. J., Tillman, E. M., Pratt, V. M., Dexter, P. R., McCoy, A. B., Orlando, L. A., Scott, S. A., Nadkarni, G. N., Horowitz, C. R., Kannry, J. L. 2021; 11 (6)


    (1) Background: Clinical decision support (CDS) is a vitally important adjunct to the implementation of pharmacogenomic-guided prescribing in clinical practice. A novel CDS was sought for the APOL1, NAT2, and YEATS4 genes to guide optimal selection of antihypertensive medications among the African American population cared for at multiple participating institutions in a clinical trial. (2) Methods: The CDS committee, made up of clinical content and CDS experts, developed a framework and contributed to the creation of the CDS using the following guiding principles: 1. medical algorithm consensus; 2. actionability; 3. context-sensitive triggers; 4. workflow integration; 5. feasibility; 6. interpretability; 7. portability; and 8. discrete reporting of lab results. (3) Results: Utilizing the principle of discrete patient laboratory and vital information, a novel CDS for APOL1, NAT2, and YEATS4 was created for use in a multi-institutional trial based on a medical algorithm consensus. The alerts are actionable and easily interpretable, clearly displaying the purpose and recommendations with pertinent laboratory results, vitals and links to ordersets with suggested antihypertensive dosages. Alerts were either triggered immediately once a provider starts to order relevant antihypertensive agents or strategically placed in workflow-appropriate general CDS sections in the electronic health record (EHR). Detailed implementation instructions were shared across institutions to achieve maximum portability. (4) Conclusions: Using sound principles, the created genetic algorithms were applied across multiple institutions. The framework outlined in this study should apply to other disease-gene and pharmacogenomic projects employing CDS.

    View details for DOI 10.3390/jpm11060480

    View details for PubMedID 34071920

  • Pharmacogenomic education among genetic counseling training programs in North America. Journal of genetic counseling Loudon, E., Scott, S. A., Rigobello, R., Scott, E. R., Zinberg, R., Naik, H. 2021


    The increasing number of genetic counselors participating directly in clinical pharmacogenomic post-test counseling prompted our evaluation of pharmacogenomic education across genetic counseling training programs in North America. Thirty-one program leadership participants from both the United States (U.S.) and Canada responded to a survey assessing pharmacogenomics education and the role of genetic counselors. Eighty-five percent of respondents agreed pharmacogenomics is currently within the scope of genetic counseling practice, and 96.3% indicated their training programs currently provide education on pharmacogenomics, with the majority reporting<7hr of education. Lectures on pharmacogenomics were the most common method for didactics; however, some programs also included practical modalities (e.g., case studies, clinical rotations) and online resources. Barriers to expanding pharmacogenomic education included the constrained timeline of training, and lack of resources and local expertise. Moreover, participants suggested that genetic counselors ideally should be able to order pharmacogenomic tests and counsel patients on pharmacogenomics, including result interpretation, as they believe pharmacogenomics does fall within the scope of practice of genetic counseling. Our novel results also confirm that training program leadership support a pharmacogenomic service delivery model that includes a combined effort between genetic counselors and pharmacists to utilize their synergistic expertise. However, this model likely still necessitates expanding pharmacogenomic didactics in genetic counseling training programs through more practical training and/or by leveraging online pharmacogenomic courses dedicated to supporting clinical implementation.

    View details for DOI 10.1002/jgc4.1417

    View details for PubMedID 33882174

  • Pharmacogenomic Determinants of Interindividual Drug Response Variability: From Discovery to Implementation. Genes Scott, S. A., Swen, J. J. 2021; 12 (3)


    Since the term "pharmacogenetics" was first published in the late 1950s by Friedrich Vogel, the field has evolved into genome-wide association studies identifying novel variants associated with drug response phenotypes, international societies and consortia dedicated to pharmacogenomic research and clinical implementation, clinical practice guidelines, and the increasing availability of pharmacogenomic tests for healthcare providers in both hospital and primary care [...].

    View details for DOI 10.3390/genes12030393

    View details for PubMedID 33801919

  • Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and European Society for Pharmacogenomics and Personalized Therapy. The Journal of molecular diagnostics : JMD Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Gaedigk, A., Hachad, H., Ji, Y., Kalman, L. V., Ly, R. C., Moyer, A. M., Scott, S. A., van Schaik, R. H., Whirl-Carrillo, M., Weck, K. E. 2021


    The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and determine a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles ("Tier 1") and an extended panel of variant alleles ("Tier 2") that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document will focus on clinical CYP2D6 PGx testing that may be applied to all CYP2D6-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide to clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform.

    View details for DOI 10.1016/j.jmoldx.2021.05.013

    View details for PubMedID 34118403

  • Machine Learning for Prediction of Stable Warfarin Dose in US Latinos and Latin Americans. Frontiers in pharmacology Steiner, H. E., Giles, J. B., Patterson, H. K., Feng, J., El Rouby, N., Claudio, K., Marcatto, L. R., Tavares, L. C., Galvez, J. M., Calderon-Ospina, C. A., Sun, X., Hutz, M. H., Scott, S. A., Cavallari, L. H., Fonseca-Mendoza, D. J., Duconge, J., Botton, M. R., Santos, P. C., Karnes, J. H. 2021; 12: 749786


    Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model's ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 × 10-15). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.

    View details for DOI 10.3389/fphar.2021.749786

    View details for PubMedID 34776967

    View details for PubMedCentralID PMC8585774

  • Novel Pharmacogenomic Locus Implicated in Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema. Journal of the American College of Cardiology Scott, S. A., Nicoletti, P. 2021; 78 (7): 710-712

    View details for DOI 10.1016/j.jacc.2021.05.050

    View details for PubMedID 34384553

  • Phased Haplotype Resolution of the SLC6A4 Promoter Using Long-Read Single Molecule Real-Time (SMRT) Sequencing. Genes Botton, M. R., Yang, Y., Scott, E. R., Desnick, R. J., Scott, S. A. 2020; 11 (11)


    The SLC6A4 gene has been implicated in psychiatric disorder susceptibility and antidepressant response variability. The SLC6A4 promoter is defined by a variable number of homologous 20-24 bp repeats (5-HTTLPR), and long (L) and short (S) alleles are associated with higher and lower expression, respectively. However, this insertion/deletion variant is most informative when considered as a haplotype with the rs25531 and rs25532 variants. Therefore, we developed a long-read single molecule real-time (SMRT) sequencing method to interrogate the SLC6A4 promoter region. A total of 120 samples were subjected to SLC6A4 long-read SMRT sequencing, primarily selected based on available short-read sequencing data. Short-read genome sequencing from the 1000 Genomes (1KG) Project (~5X) and the Genetic Testing Reference Material Coordination Program (~45X), as well as high-depth short-read capture-based sequencing (~330X), could not identify the 5-HTTLPR short (S) allele, nor could short-read sequencing phase any identified variants. In contrast, long-read SMRT sequencing unambiguously identified the 5-HTTLPR short (S) allele (frequency of 0.467) and phased SLC6A4 promoter haplotypes. Additionally, discordant rs25531 genotypes were reviewed and determined to be short-read errors. Taken together, long-read SMRT sequencing is an innovative and robust method for phased resolution of the SLC6A4 promoter, which could enable more accurate pharmacogenetic testing for both research and clinical applications.

    View details for DOI 10.3390/genes11111333

    View details for PubMedID 33198140

  • Digital Health Applications for Pharmacogenetic Clinical Trials. Genes Naik, H., Palaniappan, L., Ashley, E. A., Scott, S. A. 2020; 11 (11)


    Digital health (DH) is the use of digital technologies and data analytics to understand health-related behaviors and enhance personalized clinical care. DH is increasingly being used in clinical trials, and an important field that could potentially benefit from incorporating DH into trial design is pharmacogenetics. Prospective pharmacogenetic trials typically compare a standard care arm to a pharmacogenetic-guided therapeutic arm. These trials often require large sample sizes, are challenging to recruit into, lack patient diversity, and can have complicated workflows to deliver therapeutic interventions to both investigators and patients. Importantly, the use of DH technologies could mitigate these challenges and improve pharmacogenetic trial design and operation. Some DH use cases include (1) automatic electronic health record-based patient screening and recruitment; (2) interactive websites for participant engagement; (3) home- and tele-health visits for patient convenience (e.g., samples for lab tests, physical exams, medication administration); (4) healthcare apps to collect patient-reported outcomes, adverse events and concomitant medications, and to deliver therapeutic information to patients; and (5) wearable devices to collect vital signs, electrocardiograms, sleep quality, and other discrete clinical variables. Given that pharmacogenetic trials are inherently challenging to conduct, future pharmacogenetic utility studies should consider implementing DH technologies and trial methodologies into their design and operation.

    View details for DOI 10.3390/genes11111261

    View details for PubMedID 33114567

  • Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. Clinical pharmacology and therapeutics Lima, J. J., Thomas, C. D., Barbarino, J., Desta, Z., Van Driest, S. L., El Rouby, N., Johnson, J. A., Cavallari, L. H., Shakhnovich, V., Thacker, D. L., Scott, S. A., Schwab, M., Uppugunduri, C. R., Formea, C. M., Franciosi, J. P., Sangkuhl, K., Gaedigk, A., Klein, T. E., Gammal, R. S., Furuta, T. 2020


    Proton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of many conditions including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, H. pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by CYP2C19 into inactive metabolites, and CYP2C19 genotype has been linked to PPI exposure, efficacy, and adverse effects. We summarize the evidence from the literature and provide therapeutic recommendations for PPI prescribing based on CYP2C19 genotype (updates at The potential benefits of using CYP2C19 genotype data to guide PPI therapy include 1) identifying patients with genotypes predictive of lower plasma exposure and prescribing them a higher dose that will increase the likelihood of efficacy; and 2) identifying patients on chronic therapy with genotypes predictive of higher plasma exposure and prescribing them a decreased dose to minimize the risk of toxicity that is associated with long-term PPI use, particularly at higher plasma concentrations.

    View details for DOI 10.1002/cpt.2015

    View details for PubMedID 32770672

  • Recommendations for Clinical Warfarin Genotyping Allele Selection A Report of the Association for Molecular Pathology and the College of American Pathologists JOURNAL OF MOLECULAR DIAGNOSTICS Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Hachad, H., Ji, Y., Kalman, L. V., Ly, R. C., Moyer, A. M., Scott, S. A., Whirl-Carrillo, M., Weck, K. E. 2020; 22 (7): 847–59


    The goal of the Association for Molecular Pathology (AMP) Clinical Practice Committee's AMP Pharmacogenomics (PGx) Working Group is to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variants, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal is to promote standardization of PGx gene/allele testing across clinical laboratories. These recommendations are not to be interpreted as prescriptive but to provide a reference guide. Of note, a separate article with recommendations for CYP2C9 allele selection was previously developed by the PGx Working Group that can be applied broadly to CYP2C9-related medications. The warfarin allele recommendations in this report incorporate the previous CYP2C9 allele recommendations and additional genes and alleles that are specific to warfarin testing.

    View details for DOI 10.1016/j.jmoldx.2020.04.204

    View details for Web of Science ID 000546090500003

    View details for PubMedID 32380173

  • PharmVar GeneFocus: CYP2C19. Clinical pharmacology and therapeutics Botton, M. R., Whirl-Carrillo, M., Del Tredici, A. L., Sangkuhl, K., Cavallari, L. H., Agundez, J. A., Duconge, J., Lee, M. T., Woodahl, E. L., Claudio-Campos, K., Daly, A. K., Klein, T. E., Pratt, V. M., Scott, S. A., Gaedigk, A. 2020


    The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. CYP2C19 genetic variation impacts the metabolism of many drugs and has been associated with both, efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

    View details for DOI 10.1002/cpt.1973

    View details for PubMedID 32602114

  • Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection. Clinical and translational science Scott, S. A., Scott, E. R., Seki, Y. n., Chen, A. J., Wallsten, R. n., Owusu Obeng, A. n., Botton, M. R., Cody, N. n., Shi, H. n., Zhao, G. n., Brake, P. n., Nicoletti, P. n., Yang, Y. n., Delio, M. n., Shi, L. n., Kornreich, R. n., Schadt, E. E., Edelmann, L. n. 2020


    To develop a novel pharmacogenetic genotyping panel, a multidisciplinary team evaluated available evidence and selected 29 genes implicated in interindividual drug response variability, including 130 sequence variants and additional copy number variants (CNVs). Of the 29 genes, 11 had guidelines published by the Clinical Pharmacogenetics Implementation Consortium. Targeted genotyping and CNV interrogation were accomplished by multiplex single-base extension using the MassARRAY platform (Agena Biosciences) and multiplex ligation-dependent probe amplification (MRC Holland), respectively. Analytical validation of the panel was accomplished by a strategic combination of > 500 independent tests performed on 170 unique reference material DNA samples, which included sequence variant and CNV accuracy, reproducibility, and specimen (blood, saliva, and buccal swab) controls. Among the accuracy controls were 32 samples from the 1000 Genomes Project that were selected based on their enrichment of sequence variants included in the pharmacogenetic panel ( Coupled with publicly available samples from the Genetic Testing Reference Materials Coordination Program (GeT-RM), accuracy validation material was available for the majority (77%) of interrogated sequence variants (100% with average allele frequencies > 0.1%), as well as additional structural alleles with unique copy number signatures (e.g., CYP2D6*5, *13, *36, *68; CYP2B6*29; and CYP2C19*36). Accuracy and reproducibility for both genotyping and copy number were > 99.9%, indicating that the optimized panel platforms were precise and robust. Importantly, multi-ethnic allele frequencies of the interrogated variants indicate that the vast majority of the general population carries at least one of these clinically relevant pharmacogenetic variants, supporting the implementation of this panel for pharmacogenetic research and/or clinical implementation programs.

    View details for DOI 10.1111/cts.12844

    View details for PubMedID 32931151

  • VarCover: Allele Min-Set Cover Software. The Journal of molecular diagnostics : JMD Scott, E. R., Bansal, V. n., Meacham, C. n., Scott, S. A. 2020; 22 (2): 123–31


    To facilitate reference-material selection for clinical genetic testing laboratories, we developed VarCover, open-source software hosted on GitHub, which accepts a file of variants and returns an approximately minimum set (min-set) of samples covering the targeted alleles. VarCover employs the SetCoverPy package, sample weights, and preselection of singleton-possessing samples to efficiently solve the min-set cover problem. As a test case, we attempted to find a min-set of reference samples from the 1000 Genomes Project to cover 237 variants considered putatively pathogenic (of which 12 were classified as pathogenic or likely pathogenic) in the original 56 medically actionable genes recommended by the American College of Medical Genetics and Genomics (ACMG). The number of samples, number of alleles, and processing time were measured in subsets of the 237 target alleles. VarCover identified 140 reference-material samples from the 1000 Genomes Project covering the 237 alleles in the 56 ACMG-recommended genes. Sample weights derived from the minor allele frequency spectrum increased the number of alleles in the solution set. Preselection of samples that possessed singleton target alleles reduced computational processing time when the target set size exceeded 100 alleles. VarCover provides a simple programmatic interface for identifying an approximately min-set of reference samples, thereby reducing clinical laboratory effort and molecular genetic test-validation costs.

    View details for DOI 10.1016/j.jmoldx.2019.10.005

    View details for PubMedID 31751680

  • Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis. Clinical pharmacology and therapeutics Asiimwe, I. G., Zhang, E. J., Osanlou, R. n., Krause, A. n., Dillon, C. n., Suarez-Kurtz, G. n., Zhang, H. n., Perini, J. A., Renta, J. Y., Duconge, J. n., Cavallari, L. H., Marcatto, L. R., Beasly, M. T., Perera, M. A., Limdi, N. A., Santos, P. C., Kimmel, S. E., Lubitz, S. A., Scott, S. A., Kawai, V. K., Jorgensen, A. L., Pirmohamed, M. n. 2020; 107 (6): 1420–33


    Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.

    View details for DOI 10.1002/cpt.1755

    View details for PubMedID 31869433

    View details for PubMedCentralID PMC7217737

  • Knowledge and attitudes on pharmacogenetics among pediatricians. Journal of human genetics Rahawi, S. n., Naik, H. n., Blake, K. V., Owusu Obeng, A. n., Wasserman, R. M., Seki, Y. n., Funanage, V. L., Oishi, K. n., Scott, S. A. 2020; 65 (5): 437–44


    Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be expected to interpret and apply pharmacogenetic test results into medical care. Previous studies have identified a lack of knowledge on pharmacogenetics across many physician specialties; however, this has not been systematically assessed among pediatricians. To evaluate pediatrician knowledge, attitude, and educational interest in pharmacogenetics, we surveyed physician cohorts from both the United States (U.S.) and Japan. A total of 282 pediatricians (210 from the U.S. and 72 from Japan) participated in an anonymous survey (online or hardcopy) on pharmacogenetics knowledge, perception, and education. Over 50% of all respondents had >10 years of clinical experience and >75% had some prior education in genetics. However, <10% felt they were familiar with pharmacogenetics, which was very consistent with <20% of the U.S. pediatricians correctly responding to a codeine/CYP2D6 pharmacogenetics knowledge question and <10% of U.S. pediatricians being aware of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Despite being generally unfamiliar with pharmacogenetics, >80% of all respondents indicated that implementation of clinical pharmacogenetic testing will improve efficacy and safety, and that pediatricians should be capable of applying this testing to their practice. Moreover, the majority (83.1%) were interested in educational opportunities on pharmacogenetics, particularly on result interpretation and therapeutic recommendations. Taken together, these data indicate that although practical knowledge of pharmacogenetics among pediatricians in the U.S. and Japan is currently very low, their interest in clinical pharmacogenetics and related education is high, which will likely facilitate future implementation.

    View details for DOI 10.1038/s10038-020-0723-0

    View details for PubMedID 31983733

    View details for PubMedCentralID PMC7109006

  • Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects. American journal of medical genetics. Part A Cohen, A. S., Simotas, C. n., Webb, B. D., Shi, H. n., Khan, W. A., Edelmann, L. n., Scott, S. A., Singh, R. n. 2020; 182 (5): 1263–67


    Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD.

    View details for DOI 10.1002/ajmg.a.61537

    View details for PubMedID 32134193

  • Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos. Clinical and translational science El Rouby, N. n., Rodrigues Marcatto, L. n., Claudio, K. n., Camargo Tavares, L. n., Steiner, H. n., Botton, M. R., Lubitz, S. A., Fallon, E. N., Yee, K. n., Kaye, J. n., Scott, S. A., Karnes, J. n., Caleb Junior de Lima Santos, P. n., Duconge, J. n., Cavallari, L. H. 2020


    We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = -0.29, P < 2.0 × 10-16 ; β = -0.21, P = 4.7 × 10-7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10-4 ; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = -0.14, P = 2.0 × 10-16 ), CYP2C9 (β = -0.07, P = 5.6 × 10-10 ), and CYP4F2 (β = 0.03, P = 3 × 10-3 ), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.

    View details for DOI 10.1111/cts.12854

    View details for PubMedID 32860733

  • Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial. BMJ open Hernandez-Suarez, D. F., Melin, K. n., Marin-Maldonado, F. n., Nunez, H. J., Gonzalez, A. F., Gonzalez-Sepulveda, L. n., Rivas-Tumanyan, S. n., Naik, H. n., Ruaño, G. n., Scott, S. A., Duconge, J. n. 2020; 10 (8): e038936


    Minority populations in the USA are disproportionately affected by cardiovascular conditions. Reduced responsiveness to clopidogrel among carriers of CYP2C19 variants has been reported in patients with either coronary artery disease (CAD) or acute coronary syndrome (ACS) after the percutaneous coronary intervention (PCI). Previous studies have evaluated CYP2C19 genotyping-guided antiplatelet therapy in selected populations; however, this has yet to be tested among Hispanics. Given the paucity of clinical research on CYP2C19 and antiplatelet clinical outcomes in Hispanics, our study will test the safety and efficacy of a genetic-driven treatment algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics.This is a multicentre, prospective, non-randomised clinical trial that proposes an assessment of pharmacogenomic-guided DAPT in post-PCI Caribbean Hispanic patients with ACS or CAD. We will recruit 250 patients to be compared with a matched non-concurrent cohort of 250 clopidogrel-treated patients (standard-of-care). Major adverse cardiovascular events (MACEs) such as all-cause death, myocardial infarction (MI), stroke, coronary revascularisation, stent thrombosis and bleedings over 6 months will be the study endpoints. Among the recruited, high-risk patients will be escalated to ticagrelor and low-risk patients will remain on clopidogrel. The primary objective is to determine whether genetic-guided therapy is superior to standard of care. The secondary objective will determine if clopidogrel treatment in low-risk patients is not associated with a higher rate of MACEs compared with escalated antiplatelet therapy in high-risk patients. Patients will be enrolled up to the group's completion.Approval was obtained from the Institutional Review Board of the University of Puerto Rico Medical Sciences Campus (protocol # A4070417). The study will be carried out in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. Findings will be published in a peer-reviewed journal and controlled access to experimental data will be available.NCT03419325; Pre-results.

    View details for DOI 10.1136/bmjopen-2020-038936

    View details for PubMedID 32764090

    View details for PubMedCentralID PMC7412606

  • Clinical Pharmacogenetic Testing and the Posttest Counseling Conundrum. Clinical pharmacology and therapeutics Rigobello, R. n., Rahawi, S. n., Wallsten, R. n., Cody, N. n., Nicoletti, P. n., Owusu Obeng, A. n., Naik, H. n., Dillon, M. W., Scott, S. A. 2020; 108 (5): 924–28

    View details for DOI 10.1002/cpt.1913

    View details for PubMedID 32592592

  • A Call for Clear and Consistent Communications Regarding the Role of Pharmacogenetics in Antidepressant Pharmacotherapy. Clinical pharmacology and therapeutics Hicks, J. K., Bishop, J. R., Gammal, R. S., Sangkuhl, K., Bousman, C. A., Leeder, J. S., Llerena, A., Mueller, D. J., Ramsey, L. B., Scott, S. A., Skaar, T. C., Caudle, K. E., Klein, T. E., Gaedigk, A. 2019

    View details for DOI 10.1002/cpt.1661

    View details for PubMedID 31664715

  • Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals CLINICAL PHARMACOLOGY & THERAPEUTICS Danese, E., Raimondi, S., Montagnana, M., Tagetti, A., Langaee, T., Borgiani, P., Ciccacci, C., Carcas, A. J., Borobia, A. M., Tong, H. Y., Davila-Fajardo, C., Botton, M., Bourgeois, S., Deloukas, P., Caldwell, M. D., Burmester, J. K., Berg, R. L., Cavallari, L. H., Drozda, K., Huang, M., Zhao, L., Cen, H., Gonzalez-Conejero, R., Roldan, V., Nakamura, Y., Mushiroda, T., Gong, I. Y., Kim, R. B., Hirai, K., Itoh, K., Isaza, C., Beltran, L., Jimenez-Varo, E., Canadas-Garre, M., Giontella, A., Kringen, M. K., Haug, K., Gwak, H., Lee, K., Minuz, P., Lee, M., Lubitz, S. A., Scott, S., Mazzaccara, C., Sacchetti, L., Genc, E., Ozer, M., Pathare, A., Krishnamoorthy, R., Paldi, A., Siguret, V., Loriot, M., Kutala, V., Suarez-Kurtz, G., Perini, J., Denny, J. C., Ramirez, A. H., Mittal, B., Rathore, S., Sagreiya, H., Altman, R., Shahin, M. A., Khalifa, S., Limdi, N. A., Rivers, C., Shendre, A., Dillon, C., Suriapranata, I. M., Zhou, H., Tan, S., Tatarunas, V., Lesauskaite, V., Zhang, Y., Maitland-van der Zee, A. H., Verhoef, T., de Boer, A., Taljaard, M., Zambon, C., Pengo, V., Zhang, J., Pirmohamed, M., Johnson, J. A., Fava, C. 2019; 105 (6): 1477–91

    View details for DOI 10.1002/cpt.1323

    View details for Web of Science ID 000467751900030

  • Pharmacogene Variation Consortium Gene Introduction: NUDT15 CLINICAL PHARMACOLOGY & THERAPEUTICS Yang, J. J., Whirl-Carrillo, M., Scott, S. A., Turner, A. J., Schwab, M., Tanaka, Y., Suarez-Kurtz, G., Schaeffeler, E., Klein, T. E., Miller, N. A., Gaedigki, A. 2019; 105 (5): 1091–94

    View details for DOI 10.1002/cpt.1268

    View details for Web of Science ID 000466750900013

  • Development of a Genomic Data Flow Framework: Results of a Survey Administered to NIH-NHGRI IGNITE and eMERGE Consortia Participants. AMIA ... Annual Symposium proceedings. AMIA Symposium Dexter, P. n., Ong, H. n., Elsey, A. n., Bell, G. n., Walton, N. n., Chung, W. n., Rasmussen, L. n., Hicks, K. n., Owusu-Obeng, A. n., Scott, S. n., Ellis, S. n., Peterson, J. n. 2019; 2019: 363–70


    Precision health's more individualized molecular approach will enrich our understanding of disease etiology and patient outcomes. Universal implementation of precision health will not be feasible, however, until there is much greater automation of processes related to genomic data transmission, transformation, and interpretation. In this paper, we describe a framework for genomic data flow developed by the Clinical Informatics Work Group of the NIH National Human Genome Research Institute (NHGRI) IGNITE Network consortium. We subsequently report the results of a genomic data flow survey administered to sites funded by NIH-NHGRI for large scale genomic medicine implementations. Finally, we discuss insights and challenges identified through these survey results as they relate to both the current and a desirable future state of genomic data flow.

    View details for PubMedID 32308829

    View details for PubMedCentralID PMC7153090

  • Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clinical and translational science Caudle, K. E., Sangkuhl, K. n., Whirl-Carrillo, M. n., Swen, J. J., Haidar, C. E., Klein, T. E., Gammal, R. S., Relling, M. V., Scott, S. A., Hertz, D. L., Guchelaar, H. J., Gaedigk, A. n. 2019


    Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified-Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.

    View details for DOI 10.1111/cts.12692

    View details for PubMedID 31647186

  • Essential Characteristics of Pharmacogenomics Study Publications CLINICAL PHARMACOLOGY & THERAPEUTICS Thorn, C. F., Whirl-Carrillo, M., Hachad, H., Johnson, J. A., McDonagh, E. M., Ratain, M. J., Relling, M. V., Scott, S. A., Altman, R. B., Klein, T. E. 2019; 105 (1): 86–91

    View details for DOI 10.1002/cpt.1279

    View details for Web of Science ID 000454618200017

  • Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists. The Journal of molecular diagnostics : JMD Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Hachad, H. n., Ji, Y. n., Moyer, A. M., Scott, S. A., Whirl-Carrillo, M. n., Weck, K. E. 2019


    The goals of the Association for Molecular Pathology Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee are to define the key attributes of PGx alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for CYP2C9 testing. The Working Group considered functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. Our goal is to promote standardization of testing PGx genes/allele testing across clinical laboratories. These recommendations are not to be interpreted as restrictive but to provide a reference guide. The current document will focus on CYP2C9 testing that can be applied to all CYP2C9-related medications. A separate recommendation on warfarin PGx testing is being developed to include recommendations on CYP2C9 alleles and additional warfarin sensitivity-associated genes/alleles.

    View details for PubMedID 31075510

  • Characterization of Reference Materials for Genetic Testing of CYP2D6 Alleles: A GeT-RM Collaborative Project. The Journal of molecular diagnostics : JMD Gaedigk, A. n., Turner, A. n., Everts, R. E., Scott, S. A., Aggarwal, P. n., Broeckel, U. n., McMillin, G. A., Melis, R. n., Boone, E. C., Pratt, V. M., Kalman, L. V. 2019; 21 (6): 1034–52


    Pharmacogenetic testing increasingly is available from clinical and research laboratories. However, only a limited number of quality control and other reference materials currently are available for the complex rearrangements and rare variants that occur in the CYP2D6 gene. To address this need, the Division of Laboratory Systems, CDC-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing and research communities and the Coriell Cell Repositories (Camden, NJ), has characterized 179 DNA samples derived from Coriell cell lines. Testing included the recharacterization of 137 genomic DNAs that were genotyped in previous Genetic Testing Reference Material Coordination Program studies and 42 additional samples that had not been characterized previously. DNA samples were distributed to volunteer testing laboratories for genotyping using a variety of commercially available and laboratory-developed tests. These publicly available samples will support the quality-assurance and quality-control programs of clinical laboratories performing CYP2D6 testing.

    View details for DOI 10.1016/j.jmoldx.2019.06.007

    View details for PubMedID 31401124

    View details for PubMedCentralID PMC6854474

  • Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles. Human mutation Botton, M. R., Lu, X. n., Zhao, G. n., Repnikova, E. n., Seki, Y. n., Gaedigk, A. n., Schadt, E. E., Edelmann, L. n., Scott, S. A. 2019; 40 (11): e37–e51


    The human CYP2C locus harbors the polymorphic CYP2C18, CYP2C19, CYP2C9, and CYP2C8 genes, and of these, CYP2C19 and CYP2C9 are directly involved in the metabolism of ~15% of all medications. All variant CYP2C19 and CYP2C9 star (*) allele haplotypes currently cataloged by the Pharmacogene Variation (PharmVar) Consortium are defined by sequence variants. To determine if structural variation also occurs at the CYP2C locus, the 10q23.33 region was interrogated across deidentified clinical chromosomal microarray (CMA) data from 20,642 patients tested at two academic medical centers. Fourteen copy number variants that affected the coding region of CYP2C genes were detected in the clinical CMA cohorts, which ranged in size from 39.2 to 1,043.3 kb. Selected deletions and duplications were confirmed by MLPA or ddPCR. Analysis of the clinical CMA and an additional 78,839 cases from the Database of Genomic Variants (DGV) and ClinGen (total n = 99,481) indicated that the carrier frequency of a CYP2C structural variant is ~1 in 1,000, with ~1 in 2,000 being a CYP2C19 full gene or partial-gene deletion carrier, designated by PharmVar as CYP2C19*36 and *37, respectively. Although these structural variants are rare in the general population, their detection will likely improve metabolizer phenotype prediction when interrogated for research and/or clinical testing.

    View details for DOI 10.1002/humu.23855

    View details for PubMedID 31260137

    View details for PubMedCentralID PMC6810756

  • Prenatal cytogenomic identification and molecular refinement of compound heterozygous STRC deletion breakpoints. Molecular genetics & genomic medicine Shi, L. n., Bai, Y. n., Kharbutli, Y. n., Oza, A. M., Amr, S. S., Edelmann, L. n., Mehta, L. n., Scott, S. A. 2019; 7 (8): e806


    Here, we report the prenatal detection of a compound heterozygous deletion at chromosome 15q15.3 by clinical chromosomal microarray (CMA) testing that included the CATSPER2 male infertility gene. However, given the low resolution of CMA at this homologous locus, it was unclear if the neighboring STRC hearing loss gene was also affected. Therefore, we developed a novel allele-specific PCR strategy, which narrowed the proximal breakpoint of the maternally inherited deletion to a 310 bp interval that was 440 bp upstream from the STRC transcription start site.

    View details for DOI 10.1002/mgg3.806

    View details for PubMedID 31218851

    View details for PubMedCentralID PMC6687617

  • Interpreting and Implementing Clinical Pharmacogenetic Tests: Perspectives From Service Providers. Clinical pharmacology and therapeutics Hachad, H. n., Ramsey, L. B., Scott, S. A. 2019; 106 (2): 298–301

    View details for DOI 10.1002/cpt.1494

    View details for PubMedID 31162629

  • Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing. Genetics in medicine : official journal of the American College of Medical Genetics Cavallari, L. H., Van Driest, S. L., Prows, C. A., Bishop, J. R., Limdi, N. A., Pratt, V. M., Ramsey, L. B., Smith, D. M., Tuteja, S. n., Duong, B. Q., Hicks, J. K., Lee, J. C., Obeng, A. O., Beitelshees, A. L., Bell, G. C., Blake, K. n., Crona, D. J., Dressler, L. n., Gregg, R. A., Hines, L. J., Scott, S. A., Shelton, R. C., Weitzel, K. W., Johnson, J. A., Peterson, J. F., Empey, P. E., Skaar, T. C. 2019; 21 (10): 2255–63


    A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

    View details for DOI 10.1038/s41436-019-0484-3

    View details for PubMedID 30894703

    View details for PubMedCentralID PMC6754805

  • Familial inheritance of the 3q29 microdeletion syndrome: case report and review. BMC medical genomics Khan, W. A., Cohen, N. n., Scott, S. A., Pereira, E. M. 2019; 12 (1): 51


    The chromosome 3q29 microdeletion syndrome is characterized by a clinical phenotype that includes behavioral features consistent with autism and attention deficit hyperactivity disorder, mild to moderate developmental delay, language-based learning disabilities, and/or dysmorphic features. In addition, recent data suggest that adults with chromosome 3q29 microdeletions have a significantly increased risk for psychosis and neuropsychiatric phenotypes.We report a 3-year-old male with global developmental delay, anemia, and mild dysmorphic facial features. Clinical chromosomal microarray (CMA) testing of the proband detected a heterozygous 1.21 Mb deletion at chromosome 3q29, consistent with a diagnosis of the 3q29 microdeletion syndrome. Interestingly, subsequent parental testing determined that the pathogenic deletion was inherited from his otherwise healthy mother who had a history of learning disabilities. The chromosome 3q29 microdeletion was not detected in the healthy older sibling of the proband by CMA testing, nor was it prenatally detected in a subsequent maternal pregnancy.Our report highlights the 3q29 microdeletion syndrome as an illustrative example of the importance of a molecular diagnosis for families that harbor pathogenic copy number aberrations with variable expressivity, in particular those that also impart an increased risk for adult onset neuropsychiatric phenotypes.

    View details for DOI 10.1186/s12920-019-0497-4

    View details for PubMedID 30885185

    View details for PubMedCentralID PMC6421695

  • Integrated CYP2D6 interrogation for multiethnic copy number and tandem allele detection. Pharmacogenomics Qiao, W. n., Martis, S. n., Mendiratta, G. n., Shi, L. n., Botton, M. R., Yang, Y. n., Gaedigk, A. n., Vijzelaar, R. n., Edelmann, L. n., Kornreich, R. n., Desnick, R. J., Scott, S. A. 2019; 20 (1): 9–20


    To comprehensively interrogate CYP2D6 by integrating genotyping, copy number analysis and novel strategies to identify CYP2D6*36 and characterize CYP2D6 duplications.Genotyping of 16 CYP2D6 alleles, multiplex ligation-dependent probe amplification (MLPA) and CYP2D6*36 and duplication allele-specific genotyping were performed on 427 African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals.A novel PCR strategy determined that almost half of all CYP2D6*10 (100C>T) alleles are actually *36 (isolated or in tandem with *10) and all identified duplication alleles were characterized. Integrated results from all testing platforms enabled the refinement of genotype frequencies across all studied populations.The polymorphic CYP2D6 gene requires comprehensive interrogation to characterize allelic variation across ethnicities, which was enabled in this study by integrating multiplexed genotyping, MLPA copy number analysis, novel PCR strategies and duplication allele-specific genotyping.

    View details for DOI 10.2217/pgs-2018-0135

    View details for PubMedID 30730286

    View details for PubMedCentralID PMC6563015

  • Pharmacogene Variation Consortium Gene Introduction: NUDT15. Clinical pharmacology and therapeutics Yang, J. J., Whirl-Carrillo, M., Scott, S. A., Turner, A. J., Schwab, M., Tanaka, Y., Suarez-Kurtz, G., Schaeffeler, E., Klein, T. E., Miller, N. A., Gaedigk, A. 2018

    View details for PubMedID 30515762

  • The effect of CYP4F2, VKORC1 and CYP2C9 in influencing coumarin dose. A single patient data meta-analysis in more than 15,000 individuals. Clinical pharmacology and therapeutics Danese, E., Raimondi, S., Montagnana, M., Tagetti, A., Langaee, T., Borgiani, P., Ciccacci, C., Carcas, A. J., Borobia, A. M., Tong, H. Y., Davila-Fajardo, C., Botton, M. R., Bourgeois, S., Deloukas, P., Caldwell, M. D., Burmester, J. K., Berg, R. L., Cavallari, L. H., Drozda, K., Huang, M., Zhao, L., Cen, H., Gonzalez-Conejero, R., Roldan, V., Nakamura, Y., Mushiroda, T., Gong, I. Y., Kim, R. B., Hirai, K., Itoh, K., Isaza, C., Beltran, L., Jimenez-Varo, E., Canadas-Garre, M., Giontella, A., Kringen, M. K., Bente Foss Haug, K., Gwak, H. S., Lee, K. E., Minuz, P., Lee, M. T., Lubitz, S. A., Scott, S., Mazzaccara, C., Sacchetti, L., Genc, E., Ozer, M., Pathare, A., Krishnamoorthy, R., Paldi, A., Siguret, V., Loriot, M., Kutala, V. K., Suarez-Kurtz, G., Perini, J., Denny, J. C., Ramirez, A. H., Mittal, B., Rathore, S. S., Sagreiya, H., Altman, R., Shahin, M. H., Khalifa, S. I., Limdi, N. A., Rivers, C., Shendre, A., Dillon, C., Suriapranata, I. M., Zhou, H., Tan, S., Tatarunas, V., Lesauskaite, V., Zhang, Y., Maitland-van der Zee, A. H., Verhoef, T. I., de Boer, A., Taljaard, M., Zambon, C. F., Pengo, V., Zhang, J. E., Pirmohamed, M., Johnson, J. A., Fava, C. 2018


    The CYP4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at individual patients' level to capture the possible effect of ethnicity, gene-gene interaction or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95%CI 7-10%), with a higher effect in females, in patients taking acenocoumarol and in Whites. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30506689

  • Essential characteristics of pharmacogenomics study publications. Clinical pharmacology and therapeutics Thorn, C. F., Whirl-Carrillo, M., Hachad, H., Johnson, J. A., McDonagh, E. M., Ratain, M. J., Relling, M. V., Scott, S. A., Altman, R. B., Klein, T. E. 2018


    Pharmacogenomics (PGx) can be seen as a model for biomedical studies: it includes all disease areas of interest, spans in vitro studies to clinical trials, while focusing on the relationships between genes and drugs and the resulting phenotypes. This review will examine different characteristics of PGx study publications and provide examples of excellence in framing PGx questions and reporting their resulting data in a way that maximizes the knowledge that can be built upon them. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30406943

  • Multi-ethnic genome-wide association study for atrial fibrillation NATURE GENETICS Roselli, C., Chaffin, M. D., Weng, L., Aeschbacher, S., Ahlberg, G., Albert, C. M., Almgren, P., Alonso, A., Anderson, C. D., Aragam, K. G., Arking, D. E., Barnard, J., Bartz, T. M., Benjamin, E. J., Bihlmeyer, N. A., Bis, J. C., Bloom, H. L., Boerwinkle, E., Bottinger, E. B., Brody, J. A., Calkins, H., Campbell, A., Cappola, T. P., Carlquist, J., Chasman, D. I., Chen, L. Y., Chen, Y., Choi, E., Choi, S., Christophersen, I. E., Chung, M. K., Cole, J. W., Conen, D., Cook, J., Crijns, H. J., Cutler, M. J., Damrauer, S. M., Daniels, B. R., Darbar, D., Delgado, G., Denny, J. C., Dichgans, M., Doerr, M., Dudink, E. A., Dudley, S. C., Esa, N., Esko, T., Eskola, M., Fatkin, D., Felix, S. B., Ford, I., Franco, O. H., Geelhoed, B., Grewal, R. P., Gudnason, V., Guo, X., Gupta, N., Gustafsson, S., Gutmann, R., Hamsten, A., Harris, T. B., Hayward, C., Heckbert, S. R., Hernesniemi, J., Hocking, L. J., Hofman, A., Horimoto, A. R., Huang, J., Huang, P. L., Huffman, J., Ingelsson, E., Ipek, E., Ito, K., Jimenez-Conde, J., Johnson, R., Jukema, J., Kaeaeb, S., Kahonen, M., Kamatani, Y., Kane, J. P., Kastrati, A., Kathiresan, S., Katschnig-Winter, P., Kavousi, M., Kessler, T., Kietselaer, B. L., Kirchhof, P., Kleber, M. E., Knight, S., Krieger, J. E., Kubo, M., Launer, L. J., Laurikka, J., Lehtimaki, T., Leineweber, K., Lemaitre, R. N., Li, M., Lim, H., Lin, H. J., Lin, H., Lind, L., Lindgren, C. M., Lokki, M., London, B., Loos, R. F., Low, S., Lu, Y., Lyytikainen, L., Macfarlane, P. W., Magnusson, P. K., Mahajan, A., Malik, R., Mansur, A. J., Marcus, G. M., Margolin, L., Margulies, K. B., Maerz, W., McManus, D. D., Melander, O., Mohanty, S., Montgomery, J. A., Morley, M. P., Morris, A. P., Mueller-Nurasyid, M., Natale, A., Nazarian, S., Neumann, B., Newton-Cheh, C., Niemeijer, M. N., Nikus, K., Nilsson, P., Noordam, R., Oellers, H., Olesen, M. S., Orho-Melander, M., Padmanabhan, S., Pak, H., Pare, G., Pedersen, N. L., Pera, J., Pereira, A., Porteous, D., Psaty, B. M., Pulit, S. L., Pullinger, C. R., Rader, D. J., Refsgaard, L., Ribases, M., Ridker, P. M., Rienstra, M., Risch, L., Roden, D. M., Rosand, J., Rosenberg, M. A., Rost, N., Rotter, J. I., Saba, S., Sandhu, R. K., Schnabel, R. B., Schramm, K., Schunkert, H., Schurman, C., Scott, S. A., Seppala, I., Shaffer, C., Shah, S., Shalaby, A. A., Shim, J., Shoemaker, M., Siland, J. E., Sinisalo, J., Sinner, M. F., Slowik, A., Smith, A. V., Smith, B. H., Smith, J., Smith, J. D., Smith, N. L., Soliman, E. Z., Sotoodehnia, N., Stricker, B. H., Sun, A., Sun, H., Svendsen, J. H., Tanaka, T., Tanriverdi, K., Taylor, K. D., Teder-Laving, M., Teumer, A., Theriault, S., Trompet, S., Tucker, N. R., Tveit, A., Uitterlinden, A. G., Van Der Harst, P., Van Gelder, I. C., Van Wagoner, D. R., Verweij, N., Vlachopoulou, E., Voelker, U., Wang, B., Weeke, P. E., Weijs, B., Weiss, R., Weiss, S., Wells, Q. S., Wiggins, K. L., Wong, J. A., Woo, D., Worrall, B. B., Yang, P., Yao, J., Yoneda, Z. T., Zeller, T., Zeng, L., Lubitz, S. A., Lunetta, K. L., Ellinor, P. T. 2018; 50 (9): 1225-+


    Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

    View details for PubMedID 29892015

  • Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population. Pharmacogenomics and personalized medicine Hernandez-Suarez, D. F., Botton, M. R., Scott, S. A., Tomey, M. I., Garcia, M. J., Wiley, J. n., Villablanca, P. A., Melin, K. n., Lopez-Candales, A. n., Renta, J. Y., Duconge, J. n. 2018; 11: 95–106


    High on-treatment platelet reactivity (HTPR) to clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease.We performed a retrospective study of 111 patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU) ≥230. Genotyping testing was performed using Taqman® Genotyping Assays.The mean PRU across the cohort was 203±61 PRU (range 8-324), and 42 (38%) patients had HTPR. Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (odds ratio [OR]=1.15; 95% CI: 1.03-1.27), diabetes mellitus (OR=3.46; 95% CI: 1.05-11.43), hematocrit (OR=0.75; 95% CI: 0.65-0.87), and CYP2C19*2 (OR=4.44; 95% CI: 1.21-16.20) were the only independent predictors of HTPR.Moreover, we propose a predictive model to determine PRU values as measured by VerifyNow P2Y12 assay for the Puerto Rican Hispanic population. This model has the potential to identify Hispanic patients at higher risk for adverse events on clopidogrel.

    View details for DOI 10.2147/PGPM.S165805

    View details for PubMedID 29922082

    View details for PubMedCentralID PMC5996853

  • Multi-ethnic SULT1A1 copy number profiling with multiplex ligation-dependent probe amplification. Pharmacogenomics Vijzelaar, R. n., Botton, M. R., Stolk, L. n., Martis, S. n., Desnick, R. J., Scott, S. A. 2018; 19 (9): 761–70


    To develop a SULT1A1 multiplex ligation-dependent probe amplification assay and to investigate multi-ethnic copy number variant frequencies.A novel multiplex ligation-dependent probe amplification assay was developed and tested on 472 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals.The frequencies of atypical total copy number (i.e., greater or less than two) were 38.7% for Hispanics, 38.9% for Ashkenazi Jewish, 43.2% for Caucasians, 53.6% for Asians and 64.1% for African-Americans. Heterozygous SULT1A1 deletion carriers (slow sulfators) were most common among Caucasians (8.4%), whereas African-Americans had the highest frequencies of three or more copies (rapid sulfators; 60.9%).Different ethnic and racial populations have varying degrees of SULT1A1-mediated sulfation activity, which warrants further research and that may have utility for drug response prediction among SULT1A1-metabolized medications.

    View details for DOI 10.2217/pgs-2018-0047

    View details for PubMedID 29790428

    View details for PubMedCentralID PMC6021911

  • Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology. The Journal of molecular diagnostics : JMD Pratt, V. M., Del Tredici, A. L., Hachad, H. n., Ji, Y. n., Kalman, L. V., Scott, S. A., Weck, K. E. 2018; 20 (3): 269–76


    This document was developed by the Pharmacogenomics (PGx) Working Group of the Association for Molecular Pathology Clinical Practice Committee, whose aim is to recommend variants for inclusion in clinical pharmacogenomic testing panels. The goals of the Association for Molecular Pathology PGx Working Group are to define the key attributes of PGx alleles recommended for clinical testing and to define a minimum set of variants that should be included in clinical PGx genotyping assays. These recommendations include a minimum panel of variant alleles (tier 1) and an extended panel of variant alleles (tier 2) that will aid clinical laboratories when designing PGx assays. The Working Group considered variant allele frequencies in different populations and ethnicities, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. These CYP2C19 genotyping recommendations are the first of a series of recommendations for PGx testing. These recommendations are not to be interpreted as restrictive, but they are meant to provide a helpful guide.

    View details for DOI 10.1016/j.jmoldx.2018.01.011

    View details for PubMedID 29474986

  • Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy. Drug metabolism and personalized therapy Hernandez-Suarez, D. F., Núñez-Medina, H. n., Scott, S. A., Lopez-Candales, A. n., Wiley, J. M., Garcia, M. J., Melin, K. n., Nieves-Borrero, K. n., Rodriguez-Ruiz, C. n., Marshall, L. n., Duconge, J. n. 2018; 33 (1): 49–55


    Antiplatelet therapy with clopidogrel is recommended to reduce cardiovascular events in patients with peripheral artery disease (PAD); however, clopidogrel efficacy has not been adequately studied in this patient population. Therefore, we aimed to determine the effects of cilostazol therapy on platelet reactivity among PAD patients on clopidogrel.We performed a cross-sectional pilot study of 46 Puerto Rican patients diagnosed with PAD. The cohort was divided based on use of clopidogrel and cilostazol (n=24) or clopidogrel alone (n=22). Platelet function was measured ex vivo using the VerifyNow P2Y12 assay. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Midi Kit, which was subjected to candidate variant genotyping (CYP2C19, ABCB1, PON1 and P2RY12) using TaqMan quantitative polymerase chain reaction assays. All analyses were performed using SAS version 9.4 (SAS Institute).Among all enrolled patients, 18 (39%) had high on-treatment platelet reactivity (HTPR). The mean platelet reactivity was 207±53 (range, 78-325) with higher P2Y12 reaction units in the non-cilostazol group, 224±45 vs. 191±55 on the cilostazol group (p=0.03). No significant differences were observed in the clinical or genetic variables between the two groups. A multiple regression analysis determined that history of diabetes mellitus (p=0.03), use of cilostazol (p=0.03) and hematocrit (p=0.02) were independent predictors of platelet reactivity.In Puerto Rican PAD patients on clopidogrel therapy, history of diabetes mellitus, use of cilostazol and hematocrit are independent predictors of platelet reactivity. Adjunctive cilostazol therapy may enhance clopidogrel efficacy among PAD patients with HTPR.

    View details for DOI 10.1515/dmpt-2017-0032

    View details for PubMedID 29408797

    View details for PubMedCentralID PMC5840033

  • Cytogenomic identification and long-read single molecule real-time (SMRT) sequencing of a Bardet-Biedl Syndrome 9 (BBS9) deletion. NPJ genomic medicine Reiner, J. n., Pisani, L. n., Qiao, W. n., Singh, R. n., Yang, Y. n., Shi, L. n., Khan, W. A., Sebra, R. n., Cohen, N. n., Babu, A. n., Edelmann, L. n., Jabs, E. W., Scott, S. A. 2018; 3: 3


    Bardet-Biedl syndrome (BBS) is a recessive disorder characterized by heterogeneous clinical manifestations, including truncal obesity, rod-cone dystrophy, renal anomalies, postaxial polydactyly, and variable developmental delays. At least 20 genes have been implicated in BBS, and all are involved in primary cilia function. We report a 1-year-old male child from Guyana with obesity, postaxial polydactyly on his right foot, hypotonia, ophthalmologic abnormalities, and developmental delay, which together indicated a clinical diagnosis of BBS. Clinical chromosomal microarray (CMA) testing and high-throughput BBS gene panel sequencing detected a homozygous 7p14.3 deletion of exons 1-4 of BBS9 that was encompassed by a 17.5 Mb region of homozygosity at chromosome 7p14.2-p21.1. The precise breakpoints of the deletion were delineated to a 72.8 kb region in the proband and carrier parents by third-generation long-read single molecule real-time (SMRT) sequencing (Pacific Biosciences), which suggested non-homologous end joining as a likely mechanism of formation. Long-read SMRT sequencing of the deletion breakpoints also determined that the aberration included the neighboring RP9 gene implicated in retinitis pigmentosa; however, the clinical significance of this was considered uncertain given the paucity of reported cases with unambiguous RP9 mutations. Taken together, our study characterized a BBS9 deletion, and the identification of this shared haplotype in the parents suggests that this pathogenic aberration may be a BBS founder mutation in the Guyanese population. Importantly, this informative case also highlights the utility of long-read SMRT sequencing to map nucleotide breakpoints of clinically relevant structural variants.

    View details for DOI 10.1038/s41525-017-0042-3

    View details for PubMedID 29367880

    View details for PubMedCentralID PMC5778042

  • Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy. Clinical pharmacology and therapeutics Empey, P. E., Stevenson, J. M., Tuteja, S. n., Weitzel, K. W., Angiolillo, D. J., Beitelshees, A. L., Coons, J. C., Duarte, J. D., Franchi, F. n., Jeng, L. J., Johnson, J. A., Kreutz, R. P., Limdi, N. A., Maloney, K. A., Owusu Obeng, A. n., Peterson, J. F., Petry, N. n., Pratt, V. M., Rollini, F. n., Scott, S. A., Skaar, T. C., Vesely, M. R., Stouffer, G. A., Wilke, R. A., Cavallari, L. H., Lee, C. R. 2018; 104 (4): 664–74


    CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.

    View details for DOI 10.1002/cpt.1006

    View details for PubMedID 29280137

    View details for PubMedCentralID PMC6019555

  • Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy CLINICAL PHARMACOLOGY & THERAPEUTICS Moriyama, B., Obeng, A., Barbarino, J., Penzak, S. R., Henning, S. A., Scott, S. A., Agundez, J. G., Wingard, J. R., McLeod, H. L., Klein, T. E., Cross, S. J., Caudle, K. E., Walsh, T. J. 2017; 102 (1): 45–51

    View details for DOI 10.1002/cpt.583

    View details for Web of Science ID 000403285000008

  • The CYP2D6 VCF Translator PHARMACOGENOMICS JOURNAL Qiao, W., Wang, J., Pullman, B. S., Chen, R., Yang, Y., Scott, S. A. 2017; 17 (4): 301–3

    View details for DOI 10.1038/tpj.2016.14

    View details for Web of Science ID 000406388200001

    View details for PubMedID 26975230

    View details for PubMedCentralID PMC5025353

  • Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nature genetics Christophersen, I. E., Rienstra, M., Roselli, C., Yin, X., Geelhoed, B., Barnard, J., Lin, H., Arking, D. E., Smith, A. V., Albert, C. M., Chaffin, M., Tucker, N. R., Li, M., Klarin, D., Bihlmeyer, N. A., Low, S., Weeke, P. E., Müller-Nurasyid, M., Smith, J. G., Brody, J. A., Niemeijer, M. N., Dörr, M., Trompet, S., Huffman, J., Gustafsson, S., Schurmann, C., Kleber, M. E., Lyytikäinen, L., Seppälä, I., Malik, R., Horimoto, A. R., Perez, M., Sinisalo, J., Aeschbacher, S., Thériault, S., Yao, J., Radmanesh, F., Weiss, S., Teumer, A., Choi, S. H., Weng, L., Clauss, S., Deo, R., Rader, D. J., Shah, S. H., Sun, A., Hopewell, J. C., Debette, S., Chauhan, G., Yang, Q., Worrall, B. B., Paré, G., Kamatani, Y., Hagemeijer, Y. P., Verweij, N., Siland, J. E., Kubo, M., Smith, J. D., Van Wagoner, D. R., Bis, J. C., Perz, S., Psaty, B. M., Ridker, P. M., Magnani, J. W., Harris, T. B., Launer, L. J., Shoemaker, M. B., Padmanabhan, S., Haessler, J., Bartz, T. M., Waldenberger, M., Lichtner, P., Arendt, M., Krieger, J. E., Kähönen, M., Risch, L., Mansur, A. J., Peters, A., Smith, B. H., Lind, L., Scott, S. A., Lu, Y., Bottinger, E. B., Hernesniemi, J., Lindgren, C. M., Wong, J. A., Huang, J., Eskola, M., Morris, A. P., Ford, I., Reiner, A. P., Delgado, G., Chen, L. Y., Chen, Y. I., Sandhu, R. K., Li, M., Boerwinkle, E., Eisele, L., Lannfelt, L., Rost, N., Anderson, C. D., Taylor, K. D., Campbell, A., Magnusson, P. K., Porteous, D., Hocking, L. J., Vlachopoulou, E., Pedersen, N. L., Nikus, K., Orho-Melander, M., Hamsten, A., Heeringa, J., Denny, J. C., Kriebel, J., Darbar, D., Newton-Cheh, C., Shaffer, C., Macfarlane, P. W., Heilmann-Heimbach, S., Almgren, P., Huang, P. L., Sotoodehnia, N., Soliman, E. Z., Uitterlinden, A. G., Hofman, A., Franco, O. H., Völker, U., Jöckel, K., Sinner, M. F., Lin, H. J., Guo, X., Dichgans, M., Ingelsson, E., Kooperberg, C., Melander, O., Loos, R. J., Laurikka, J., Conen, D., Rosand, J., van der Harst, P., Lokki, M., Kathiresan, S., Pereira, A., Jukema, J. W., Hayward, C., Rotter, J. I., März, W., Lehtimäki, T., Stricker, B. H., Chung, M. K., Felix, S. B., Gudnason, V., Alonso, A., Roden, D. M., Kääb, S., Chasman, D. I., Heckbert, S. R., Benjamin, E. J., Tanaka, T., Lunetta, K. L., Lubitz, S. A., Ellinor, P. T. 2017; 49 (6): 946-952


    Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

    View details for DOI 10.1038/ng.3843

    View details for PubMedID 28416818

  • Clinical pharmacogenetics implementation consortium (cpic) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clinical pharmacology & therapeutics Johnson, J. A., Caudle, K. E., Gong, L., Whirl-Carrillo, M., Stein, C. M., Scott, S. A., Lee, M. T., Gage, B. F., Kimmel, S. E., Perera, M. A., Anderson, J. L., Pirmohamed, M., Klein, T. E., Limdi, N. A., Cavallari, L. H., Wadelius, M. 2017


    This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

    View details for DOI 10.1002/cpt.668

    View details for PubMedID 28198005

  • Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC) GENETICS IN MEDICINE Caudle, K. E., Dunnenberger, H. M., Freimuth, R. R., Peterson, J. F., Burlison, J. D., Whirl-Carrillo, M., Scott, S. A., Rehm, H. L., Williams, M. S., Klein, T. E., Relling, M. V., Hoffman, J. M. 2017; 19 (2): 215-223


    Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes.Terms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain a consensus and agree on uniform terms among pharmacogenetic experts.Experts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n = 58) participated. After completion of five surveys, a consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms.The proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support.Genet Med advance online publication 21 July 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.87.

    View details for DOI 10.1038/gim.2016.87

    View details for Web of Science ID 000393534200011

  • Modeling susceptibility to drug-induced long QT with a panel of subject-specific induced pluripotent stem cells ELIFE Stillitano, F., Hansen, J., Kong, C., Karakikes, I., Faunck-Brentano, C., Geng, L., Scott, S., Reynier, S., Wu, M., Valogne, Y., Desseaux, C., Salem, J., Jeziorowska, D., Zahr, N., Li, R., Iyengar, R., Hajjar, R. J., Hulot, J. 2017; 6


    A large number of drugs can induce prolongation of cardiac repolarization and life-threatening cardiac arrhythmias. The prediction of this side effect is however challenging as it usually develops in some genetically predisposed individuals with normal cardiac repolarization at baseline. Here, we describe a platform based on a genetically diverse panel of induced pluripotent stem cells (iPSCs) that reproduces susceptibility to develop a cardiotoxic drug response. We generated iPSC-derived cardiomyocytes from patients presenting in vivo with extremely low or high changes in cardiac repolarization in response to a pharmacological challenge with sotalol. In vitro, the responses to sotalol were highly variable but strongly correlated to the inter-individual differences observed in vivo. Transcriptomic profiling identified dysregulation of genes (DLG2, KCNE4, PTRF, HTR2C, CAMKV) involved in downstream regulation of cardiac repolarization machinery as underlying high sensitivity to sotalol. Our findings offer novel insights for the development of iPSC-based screening assays for testing individual drug reactions.

    View details for DOI 10.7554/eLife.19406

    View details for Web of Science ID 000393403900001

    View details for PubMedID 28134617

    View details for PubMedCentralID PMC5279943

  • DNA Methylation Profiling Using Long-Read Single Molecule Real-Time Bisulfite Sequencing (SMRT-BS). Methods in molecular biology (Clifton, N.J.) Yang, Y. n., Scott, S. A. 2017; 1654: 125–34


    For the past two decades, bisulfite sequencing has been a widely used method for quantitative CpG methylation detection of genomic DNA. Coupled with PCR amplicon cloning, bisulfite Sanger sequencing allows for allele-specific CpG methylation assessment; however, its time-consuming protocol and inability to multiplex has recently been overcome by next-generation bisulfite sequencing techniques. Although high-throughput sequencing platforms have enabled greater accuracy in CpG methylation quantitation as a result of increased bisulfite sequencing depth, most common sequencing platforms generate reads that are similar in length to the typical bisulfite PCR size range (~300-500 bp). Using the Pacific Biosciences (PacBio) sequencing platform, we developed single molecule real-time bisulfite sequencing (SMRT-BS), which is an accurate targeted CpG methylation analysis method capable of a high degree of multiplexing and long read lengths. SMRT-BS is reproducible and was found to be concordant with other lower throughput quantitative CpG methylation methods. Moreover, the ability to sequence up to ~1.5-2.0 kb amplicons, when coupled with an optimized bisulfite-conversion protocol, allows for more thorough assessment of CpG islands and increases the capacity for studying the relationship between single nucleotide variants and allele-specific CpG methylation.

    View details for DOI 10.1007/978-1-4939-7231-9_8

    View details for PubMedID 28986786

  • Institutional profile: translational pharmacogenomics at the Icahn School of Medicine at Mount Sinai. Pharmacogenomics Scott, S. A., Owusu Obeng, A. n., Botton, M. R., Yang, Y. n., Scott, E. R., Ellis, S. B., Wallsten, R. n., Kaszemacher, T. n., Zhou, X. n., Chen, R. n., Nicoletti, P. n., Naik, H. n., Kenny, E. E., Vega, A. n., Waite, E. n., Diaz, G. A., Dudley, J. n., Halperin, J. L., Edelmann, L. n., Kasarskis, A. n., Hulot, J. S., Peter, I. n., Bottinger, E. P., Hirschhorn, K. n., Sklar, P. n., Cho, J. H., Desnick, R. J., Schadt, E. E. 2017; 18 (15): 1381–86


    For almost 50 years, the Icahn School of Medicine at Mount Sinai has continually invested in genetics and genomics, facilitating a healthy ecosystem that provides widespread support for the ongoing programs in translational pharmacogenomics. These programs can be broadly cataloged into discovery, education, clinical implementation and testing, which are collaboratively accomplished by multiple departments, institutes, laboratories, companies and colleagues. Focus areas have included drug response association studies and allele discovery, multiethnic pharmacogenomics, personalized genotyping and survey-based education programs, pre-emptive clinical testing implementation and novel assay development. This overview summarizes the current state of translational pharmacogenomics at Mount Sinai, including a future outlook on the forthcoming expansions in overall support, research and clinical programs, genomic technology infrastructure and the participating faculty.

    View details for DOI 10.2217/pgs-2017-0137

    View details for PubMedID 28982267

    View details for PubMedCentralID PMC5694020

  • Clinical determinants of clopidogrel responsiveness in a heterogeneous cohort of Puerto Rican Hispanics. Therapeutic advances in cardiovascular disease Hernandez-Suarez, D. F., Scott, S. A., Tomey, M. I., Melin, K. n., Lopez-Candales, A. n., Buckley, C. E., Duconge, J. n. 2017; 11 (9): 235–41


    Clopidogrel is by far the most prescribed platelet adenosine diphosphate (ADP) antagonist in Puerto Rico despite the advent of newer agents (prasugrel and ticagrelor). Given the paucity of data on clopidogrel responsiveness in Hispanics, we sought to determine the association between clinical characteristics and platelet reactivity in Puerto Rican patients on clopidogrel therapy.A total of 100 Puerto Rican patients on clopidogrel therapy were enrolled and allocated into two groups: Group I, without high on-treatment platelet reactivity (HTPR); and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay.The cohort was comprised of Hispanic patients with coronary artery disease (57%), peripheral artery disease (32%), carotid artery stenosis (7%), cerebral artery aneurysm (2%), and stroke (2%). Mean platelet reactivity was 200 ± 61 P2Y12 reaction units (PRUs) (range: 8-324), and 35% of patients had HTPR (PRUs ⩾ 230). Multivariable logistic regression analysis determined that diabetes mellitus (DM) [odds ratio (OR) = 3.27; 95% confidence interval (CI): 1.20-8.96], use of proton-pump inhibitors (PPIs) (OR = 3.60; 95% CI: 1.09-11.82), and calcium channel blockers (CCBs) (OR = 3.10; 95% CI: 1.09-8.83) were independent predictors of HTPR ( p < 0.05) after adjusting for other clinical variables.In a sample of 100 Puerto Rican Hispanic patients on clopidogrel, 35% had HTPR. Furthermore, DM, PPIs and CCBs predicted HTPR. Clinical outcome data are needed to identify appropriate PRU thresholds for risk prediction in the Puerto Rican population.

    View details for DOI 10.1177/1753944717718718

    View details for PubMedID 28675986

    View details for PubMedCentralID PMC5555769

  • Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study. Frontiers in pharmacology Claudio-Campos, K. n., Labastida, A. n., Ramos, A. n., Gaedigk, A. n., Renta-Torres, J. n., Padilla, D. n., Rivera-Miranda, G. n., Scott, S. A., Ruaño, G. n., Cadilla, C. L., Duconge-Soler, J. n. 2017; 8: 347


    Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

    View details for DOI 10.3389/fphar.2017.00347

    View details for PubMedID 28638342

    View details for PubMedCentralID PMC5461284

  • Concordance between Research Sequencing and Clinical Pharmacogenetic Genotyping in the eMERGE-PGx Study. The Journal of molecular diagnostics : JMD Rasmussen-Torvik, L. J., Almoguera, B. n., Doheny, K. F., Freimuth, R. R., Gordon, A. S., Hakonarson, H. n., Hawkins, J. B., Husami, A. n., Ivacic, L. C., Kullo, I. J., Linderman, M. D., Manolio, T. A., Obeng, A. O., Pellegrino, R. n., Prows, C. A., Ritchie, M. D., Smith, M. E., Stallings, S. C., Wolf, W. A., Zhang, K. n., Scott, S. A. 2017; 19 (4): 561–66


    There has been extensive debate about both the necessity of orthogonal confirmation of next-generation sequencing (NGS) results in Clinical Laboratory Improvement Amendments-approved laboratories and return of research NGS results to participants enrolled in research studies. In eMERGE-PGx, subjects underwent research NGS using PGRNseq and orthogonal targeted genotyping in clinical laboratories, which prompted a comparison of genotyping results between platforms. Concordance (percentage agreement) was reported for 4077 samples tested across nine combinations of research and clinical laboratories. Retesting was possible on a subset of 1792 samples, and local laboratory directors determined sources of genotype discrepancy. Research NGS and orthogonal clinical genotyping had an overall per sample concordance rate of 0.972 and per variant concordance rate of 0.997. Genotype discrepancies attributed to research NGS were because of sample switching (preanalytical errors), whereas the majority of genotype discrepancies (92.3%) attributed to clinical genotyping were because of allele dropout as a result of rare variants interfering with primer hybridization (analytical errors). These results highlight the analytical quality of clinically significant pharmacogenetic variants derived from NGS and reveal important areas for research and clinical laboratories to address with quality management programs.

    View details for DOI 10.1016/j.jmoldx.2017.04.002

    View details for PubMedID 28502727

    View details for PubMedCentralID PMC5500823

  • Sequencing the CYP2D6 gene: from variant allele discovery to clinical pharmacogenetic testing. Pharmacogenomics Yang, Y. n., Botton, M. R., Scott, E. R., Scott, S. A. 2017; 18 (7): 673–85


    CYP2D6 is one of the most studied enzymes in the field of pharmacogenetics. The CYP2D6 gene is highly polymorphic with over 100 catalogued star (*) alleles, and clinical CYP2D6 testing is increasingly accessible and supported by practice guidelines. However, the degree of variation at the CYP2D6 locus and homology with its pseudogenes make interrogating CYP2D6 by short-read sequencing challenging. Moreover, accurate prediction of CYP2D6 metabolizer status necessitates analysis of duplicated alleles when an increased copy number is detected. These challenges have recently been overcome by long-read CYP2D6 sequencing; however, such platforms are not widely available. This review highlights the genomic complexities of CYP2D6, current sequencing methods and the evolution of CYP2D6 from allele discovery to clinical pharmacogenetic testing.

    View details for DOI 10.2217/pgs-2017-0033

    View details for PubMedID 28470112

    View details for PubMedCentralID PMC5591463

  • Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans. Journal of the American College of Cardiology Nadkarni, G. N., Galarneau, G. n., Ellis, S. B., Nadukuru, R. n., Zhang, J. n., Scott, S. A., Schurmann, C. n., Li, R. n., Rasmussen-Torvik, L. J., Kho, A. N., Hayes, M. G., Pacheco, J. A., Manolio, T. A., Chisholm, R. L., Roden, D. M., Denny, J. C., Kenny, E. E., Bottinger, E. P. 2017; 69 (12): 1564–74


    African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs.This study assessed the APOL1 risk alleles' association with blood pressure traits in AAs.The discovery cohort included 5,204 AA participants from Mount Sinai's BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles' association with blood pressure-related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta-analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate.There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [pcom] = 1.9 × 10-5). APOL1 risk alleles were associated with overall SBP (pcom = 7.0 × 10-8) and diastolic blood pressure (pcom = 2.8 × 10-4). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 ± 0.44 mm Hg (pcom = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range.APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model.

    View details for DOI 10.1016/j.jacc.2017.01.040

    View details for PubMedID 28335839

    View details for PubMedCentralID PMC5479565

  • Maternal uniparental disomy of chromosome 15 and concomitant STRC and CATSPER2 deletion-mediated deafness-infertility syndrome. American journal of medical genetics. Part A Karger, L. n., Khan, W. A., Calabio, R. n., Singh, R. n., Xiang, B. n., Babu, A. n., Cohen, N. n., Yang, A. C., Scott, S. A. 2017; 173 (5): 1436–39

    View details for DOI 10.1002/ajmg.a.38154

    View details for PubMedID 28317263

    View details for PubMedCentralID PMC5397338

  • Chromosomal Microarray Detection of Constitutional Copy Number Variation Using Saliva DNA. The Journal of molecular diagnostics : JMD Reiner, J. n., Karger, L. n., Cohen, N. n., Mehta, L. n., Edelmann, L. n., Scott, S. A. 2017; 19 (3): 397–403


    Chromosomal microarray (CMA) testing to detect copy number aberrations among individuals with multiple congenital anomalies and/or developmental delay is typically performed on peripheral blood DNA. However, the use of saliva DNA may be preferred for some patients, which prompted our validation study using six saliva DNA samples with a range of bacterial content (approximately 3% to 21%) and 20 paired blood and saliva specimens on the Agilent Technologies, Illumina, and Affymetrix CMA platforms. Ten of the 20 paired specimens were previously determined to carry clinically significant copy number aberrations by clinical CMA testing on blood DNA (100 kb to 2.56 Mb; five deletions, eight duplications). Notably, the quality of saliva DNA (DNA Genotek) was equivalent to blood DNA regardless of bacterial content, as was CMA quality and single-nucleotide polymorphism genotyping quality with all CMA platforms. The number of copy number variants and absence of heterozygosity regions detected by CMA were comparable between paired blood and saliva DNA and, more important, all 13 clinically significant copy number aberrations were detected in saliva DNA by all CMA platforms. These data confirm that the quality of saliva DNA is comparable to blood DNA regardless of bacterial content, including important CMA and single-nucleotide polymorphism quality metrics, and that saliva DNA is a reliable alternative for the detection of clinically significant copy number aberrations by clinical CMA testing.

    View details for DOI 10.1016/j.jmoldx.2016.11.006

    View details for PubMedID 28315673

    View details for PubMedCentralID PMC5417105

  • Implementing Algorithm-Guided Warfarin Dosing in an Ethnically Diverse Patient Population Using Electronic Health Records and Preemptive CYP2C9 and VKORC1 Genetic Testing CLINICAL PHARMACOLOGY & THERAPEUTICS Obeng, A., Kaszemacher, T., Abul-Husn, N. S., Gottesman, O., Vega, A., Waite, E., Myers, K., Cho, J., Bottinger, E. P., Ellis, S. B., Scott, S. A. 2016; 100 (5): 427–30


    Implementation of pharmacogenetic-guided warfarin dosing has been hindered by inconsistent results from reported clinical trials and a lack of available algorithms that include alleles prevalent in non-white populations. However, current evidence indicates that algorithm-guided dosing is more accurate than empirical dosing. To facilitate multiethnic algorithm-guided warfarin dosing using preemptive genetic testing, we developed a strategy that accounts for the complexity of race and leverages electronic health records for algorithm variables and deploying point-of-care dose recommendations.

    View details for DOI 10.1002/cpt.425

    View details for Web of Science ID 000386135800011

    View details for PubMedID 27393744

    View details for PubMedCentralID PMC5638436

  • Exome Sequencing of Extreme Clopidogrel Response Phenotypes Identifies B4GALT2 as a Determinant of On-Treatment Platelet Reactivity CLINICAL PHARMACOLOGY & THERAPEUTICS Scott, S. A., Collet, J., Baber, U., Yang, Y., Peter, I., Linderman, M., Sload, J., Qiao, W., Kini, A. S., Sharma, S. K., Desnick, R. J., Fuster, V., Hajjar, R. J., Montalescot, G., Hulot, J. 2016; 100 (3): 287–94


    Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort (n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation (P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery (P = 0.0298) and replication (n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion.

    View details for DOI 10.1002/cpt.401

    View details for Web of Science ID 000382732800022

    View details for PubMedID 27213804

    View details for PubMedCentralID PMC4982803

  • Genetic Variation Among 82 Pharmacogenes: The PGRNseq Data From the eMERGE Network CLINICAL PHARMACOLOGY & THERAPEUTICS Bush, W. S., Crosslin, D. R., Owusu-Obeng, A., Wallace, J., Almoguera, B., Basford, M. A., Bielinski, S. J., Carrell, D. S., Connolly, J. J., Crawford, D., Doheny, K. F., Gallego, C. J., Gordon, A. S., Keating, B., Kirby, J., Kitchner, T., Manzi, S., Mejia, A. R., Pan, V., Perry, C. L., Peterson, J. F., Prows, C. A., Ralston, J., Scott, S. A., Scrol, A., Smith, M., Stallings, S. C., Veldhuizen, T., Wolf, W., Volpi, S., Wiley, K., Li, R., Manolio, T., Bottinger, E., Brilliant, M. H., Carey, D., Chisholm, R. L., Chute, C. G., Haines, J. L., Hakonarson, H., Harley, J. B., Holm, I. A., Kullo, I. J., Jarvik, G. P., Larson, E. B., McCarty, C. A., Williams, M. S., Denny, J. C., Rasmussen-Torvik, L. J., Roden, D. M., Ritchie, M. D. 2016; 100 (2): 160–69


    Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

    View details for DOI 10.1002/cpt.350

    View details for Web of Science ID 000379336900018

    View details for PubMedID 26857349

    View details for PubMedCentralID PMC5010878

  • Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genetics in medicine Caudle, K. E., Dunnenberger, H. M., Freimuth, R. R., Peterson, J. F., Burlison, J. D., Whirl-Carrillo, M., Scott, S. A., Rehm, H. L., Williams, M. S., Klein, T. E., Relling, M. V., Hoffman, J. M. 2016


    Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes.Terms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain a consensus and agree on uniform terms among pharmacogenetic experts.Experts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n = 58) participated. After completion of five surveys, a consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms.The proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support.Genet Med advance online publication 21 July 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.87.

    View details for DOI 10.1038/gim.2016.87

    View details for PubMedID 27441996

  • Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. Clinical pharmacology & therapeutics Kalman, L. V., Agúndez, J., Appell, M. L., Black, J. L., Bell, G. C., Boukouvala, S., Bruckner, C., Bruford, E., Caudle, K., Coulthard, S. A., Daly, A. K., Tredici, A. D., den Dunnen, J. T., Drozda, K., Everts, R. E., Flockhart, D., Freimuth, R. R., Gaedigk, A., Hachad, H., Hartshorne, T., Ingelman-Sundberg, M., Klein, T. E., Lauschke, V. M., Maglott, D. R., McLeod, H. L., McMillin, G. A., Meyer, U. A., Müller, D. J., Nickerson, D. A., Oetting, W. S., Pacanowski, M., Pratt, V. M., RELLING, M. V., Roberts, A., Rubinstein, W. S., Sangkuhl, K., Schwab, M., Scott, S. A., Sim, S. C., Thirumaran, R. K., Toji, L. H., Tyndale, R. F., van Schaik, R., Whirl-Carrillo, M., Yeo, K., Zanger, U. M. 2016; 99 (2): 172-185


    This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

    View details for DOI 10.1002/cpt.280

    View details for PubMedID 26479518

    View details for PubMedCentralID PMC4724253

  • A de novo 2.78-Mb duplication on chromosome 21q22.11 implicates candidate genes in the partial trisomy 21 phenotype. NPJ genomic medicine Weisfeld-Adams, J. D., Tkachuk, A. K., Maclean, K. N., Meeks, N. L., Scott, S. A. 2016; 1


    Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) and in the majority of cases is the result of complete trisomy 21. The hypothesis that the characteristic DS clinical features are due to a single DS critical region (DSCR) at distal chromosome 21q has been refuted by recently reported segmental trisomy 21 cases characterised by microarray-based comparative genomic hybridisation (aCGH). These rare cases have implicated multiple regions on chromosome 21 in the aetiology of distinct features of DS; however, the map of chromosome 21 copy-number aberrations and their associated phenotypes remains incompletely defined. We report a child with ID who was deemed very high risk for DS on antenatal screening (1 in 13) and has partial, but distinct, dysmorphologic features of DS without congenital heart disease (CHD). Oligonucleotide aCGH testing of the proband detected a previously unreported de novo 2.78-Mb duplication on chromosome 21q22.11 that includes 16 genes; however, this aberration does not harbour any of the historical DSCR genes (APP, DSCR1, DYRK1A and DSCAM). This informative case implicates previously under-recognised candidate genes (SOD1, SYNJ1 and ITSN1) in the pathogenesis of specific DS clinical features and supports a critical region for CHD located more distal on chromosome 21q. In addition, this unique case illustrates how the increasing resolution of microarray and high-throughput sequencing technologies can continue to reveal new biology and enhance understanding of widely studied genetic diseases that were originally described over 50 years ago.

    View details for DOI 10.1038/npjgenmed.2016.3

    View details for PubMedID 27840696

    View details for PubMedCentralID PMC5102301

  • Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. The lancet. Psychiatry Ruderfer, D. M., Charney, A. W., Readhead, B. n., Kidd, B. A., Kähler, A. K., Kenny, P. J., Keiser, M. J., Moran, J. L., Hultman, C. M., Scott, S. A., Sullivan, P. F., Purcell, S. M., Dudley, J. T., Sklar, P. n. 2016; 3 (4): 350–57


    Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia.We defined schizophrenia risk loci as genomic regions reaching genome-wide significance in the latest Psychiatric Genomics Consortium schizophrenia genome-wide association study (GWAS) of 36 989 cases and 113 075 controls and loss of function variants observed only once among 5079 individuals in an exome-sequencing study of 2536 schizophrenia cases and 2543 controls (Swedish Schizophrenia Study). Using two large and orthogonally created databases, we collated drug targets into 167 gene sets targeted by pharmacologically similar drugs and examined enrichment of schizophrenia risk loci in these sets. We further linked the exome-sequenced data with a national drug registry (the Swedish Prescribed Drug Register) to assess the contribution of rare variants to treatment response, using clozapine prescription as a proxy for treatment resistance.We combined results from testing rare and common variation and, after correction for multiple testing, two gene sets were associated with schizophrenia risk: agents against amoebiasis and other protozoal diseases (106 genes, p=0·00046, pcorrected =0·024) and antipsychotics (347 genes, p=0·00078, pcorrected=0·046). Further analysis pointed to antipsychotics as having independent enrichment after removing genes that overlapped these two target sets. We noted significant enrichment both in known targets of antipsychotics (70 genes, p=0·0078) and novel predicted targets (277 genes, p=0·019). Patients with treatment-resistant schizophrenia had an excess of rare disruptive variants in gene targets of antipsychotics (347 genes, p=0·0067) and in genes with evidence for a role in antipsychotic efficacy (91 genes, p=0·0029).Our results support genetic overlap between schizophrenia pathogenesis and antipsychotic mechanism of action. This finding is consistent with treatment efficacy being polygenic and suggests that single-target therapeutics might be insufficient. We provide evidence of a role for rare functional variants in antipsychotic treatment response, pointing to a subset of patients where their genetic information could inform treatment. Finally, we present a novel framework for identifying treatments from genetic data and improving our understanding of therapeutic mechanism.US National Institutes of Health.

    View details for DOI 10.1016/S2215-0366(15)00553-2

    View details for PubMedID 26915512

    View details for PubMedCentralID PMC4982509

  • Analytical Validation of a Personalized Medicine APOL1 Genotyping Assay for Nondiabetic Chronic Kidney Disease Risk Assessment. The Journal of molecular diagnostics : JMD Zhang, J. n., Fedick, A. n., Wasserman, S. n., Zhao, G. n., Edelmann, L. n., Bottinger, E. P., Kornreich, R. n., Scott, S. A. 2016; 18 (2): 260–66


    The incidence of chronic kidney disease (CKD) varies by ancestry, with African Americans (AA) having a threefold to fourfold higher rate than whites. Notably, two APOL1 alleles, termed G1 [c.(1072A>G; 1200T>G)] and G2 (c.1212_1217del6), are strongly associated with higher rates of nondiabetic CKD and an increased risk for hypertensive end-stage renal disease. This has prompted the opportunity to implement APOL1 testing to identify at-risk patients and modify other risk factors to reduce the progression of CKD to end-stage renal disease. We developed an APOL1 genotyping assay using multiplex allele-specific primer extension, and validated using 58 positive and negative controls. Genotyping results were completely concordant with Sanger sequencing, and both triplicate interrun and intrarun genotyping results were completely concordant. Multiethnic APOL1 allele frequencies were also determined by genotyping 7059 AA, Hispanic, and Asian individuals from the New York City metropolitan area. The AA, Hispanic, and Asian APOL1 G1 and G2 allele frequencies were 0.22 and 0.13, 0.037 and 0.025, and 0.013 and 0.004, respectively. Notably, approximately 14% of the AA population carried two risk alleles and are at increased risk for CKD, compared with <1% of the Hispanic and Asian populations. This novel APOL1 genotyping assay is robust and highly accurate, and represents one of the first personalized medicine clinical genetic tests for disease risk prediction.

    View details for DOI 10.1016/j.jmoldx.2015.11.003

    View details for PubMedID 26773863

    View details for PubMedCentralID PMC4816711

  • Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. JAMA Van Driest, S. L., Wells, Q. S., Stallings, S. n., Bush, W. S., Gordon, A. n., Nickerson, D. A., Kim, J. H., Crosslin, D. R., Jarvik, G. P., Carrell, D. S., Ralston, J. D., Larson, E. B., Bielinski, S. J., Olson, J. E., Ye, Z. n., Kullo, I. J., Abul-Husn, N. S., Scott, S. A., Bottinger, E. n., Almoguera, B. n., Connolly, J. n., Chiavacci, R. n., Hakonarson, H. n., Rasmussen-Torvik, L. J., Pan, V. n., Persell, S. D., Smith, M. n., Chisholm, R. L., Kitchner, T. E., He, M. M., Brilliant, M. H., Wallace, J. R., Doheny, K. F., Shoemaker, M. B., Li, R. n., Manolio, T. A., Callis, T. E., Macaya, D. n., Williams, M. S., Carey, D. n., Kapplinger, J. D., Ackerman, M. J., Ritchie, M. D., Denny, J. C., Roden, D. M. 2016; 315 (1): 47–57


    Large-scale DNA sequencing identifies incidental rare variants in established Mendelian disease genes, but the frequency of related clinical phenotypes in unselected patient populations is not well established. Phenotype data from electronic medical records (EMRs) may provide a resource to assess the clinical relevance of rare variants.To determine the clinical phenotypes from EMRs for individuals with variants designated as pathogenic by expert review in arrhythmia susceptibility genes.This prospective cohort study included 2022 individuals recruited for nonantiarrhythmic drug exposure phenotypes from October 5, 2012, to September 30, 2013, for the Electronic Medical Records and Genomics Network Pharmacogenomics project from 7 US academic medical centers. Variants in SCN5A and KCNH2, disease genes for long QT and Brugada syndromes, were assessed for potential pathogenicity by 3 laboratories with ion channel expertise and by comparison with the ClinVar database. Relevant phenotypes were determined from EMRs, with data available from 2002 (or earlier for some sites) through September 10, 2014.One or more variants designated as pathogenic in SCN5A or KCNH2.Arrhythmia or electrocardiographic (ECG) phenotypes defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, ECG data, and manual EMR review.Among 2022 study participants (median age, 61 years [interquartile range, 56-65 years]; 1118 [55%] female; 1491 [74%] white), a total of 122 rare (minor allele frequency <0.5%) nonsynonymous and splice-site variants in 2 arrhythmia susceptibility genes were identified in 223 individuals (11% of the study cohort). Forty-two variants in 63 participants were designated potentially pathogenic by at least 1 laboratory or ClinVar, with low concordance across laboratories (Cohen κ = 0.26). An ICD-9 code for arrhythmia was found in 11 of 63 (17%) variant carriers vs 264 of 1959 (13%) of those without variants (difference, +4%; 95% CI, -5% to +13%; P = .35). In the 1270 (63%) with ECGs, corrected QT intervals were not different in variant carriers vs those without (median, 429 vs 439 milliseconds; difference, -10 milliseconds; 95% CI, -16 to +3 milliseconds; P = .17). After manual review, 22 of 63 participants (35%) with designated variants had any ECG or arrhythmia phenotype, and only 2 had corrected QT interval longer than 500 milliseconds.Among laboratories experienced in genetic testing for cardiac arrhythmia disorders, there was low concordance in designating SCN5A and KCNH2 variants as pathogenic. In an unselected population, the putatively pathogenic genetic variants were not associated with an abnormal phenotype. These findings raise questions about the implications of notifying patients of incidental genetic findings.

    View details for DOI 10.1001/jama.2015.17701

    View details for PubMedID 26746457

    View details for PubMedCentralID PMC4758131

  • Characterization of 137 Genomic DNA Reference Materials for 28 Pharmacogenetic Genes: A GeT-RM Collaborative Project. The Journal of molecular diagnostics : JMD Pratt, V. M., Everts, R. E., Aggarwal, P. n., Beyer, B. N., Broeckel, U. n., Epstein-Baak, R. n., Hujsak, P. n., Kornreich, R. n., Liao, J. n., Lorier, R. n., Scott, S. A., Smith, C. H., Toji, L. H., Turner, A. n., Kalman, L. V. 2016; 18 (1): 109–23


    Pharmacogenetic testing is increasingly available from clinical laboratories. However, only a limited number of quality control and other reference materials are currently available to support clinical testing. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, has characterized 137 genomic DNA samples for 28 genes commonly genotyped by pharmacogenetic testing assays (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP4F2, DPYD, GSTM1, GSTP1, GSTT1, NAT1, NAT2, SLC15A2, SLC22A2, SLCO1B1, SLCO2B1, TPMT, UGT1A1, UGT2B7, UGT2B15, UGT2B17, and VKORC1). One hundred thirty-seven Coriell cell lines were selected based on ethnic diversity and partial genotype characterization from earlier testing. DNA samples were coded and distributed to volunteer testing laboratories for targeted genotyping using a number of commercially available and laboratory developed tests. Through consensus verification, we confirmed the presence of at least 108 variant pharmacogenetic alleles. These samples are also being characterized by other pharmacogenetic assays, including next-generation sequencing, which will be reported separately. Genotyping results were consistent among laboratories, with most differences in allele assignments attributed to assay design and variability in reported allele nomenclature, particularly for CYP2D6, UGT1A1, and VKORC1. These publicly available samples will help ensure the accuracy of pharmacogenetic testing.

    View details for DOI 10.1016/j.jmoldx.2015.08.005

    View details for PubMedID 26621101

    View details for PubMedCentralID PMC4695224

  • Long-Read Single Molecule Real-Time Full Gene Sequencing of Cytochrome P450-2D6. Human mutation Qiao, W. n., Yang, Y. n., Sebra, R. n., Mendiratta, G. n., Gaedigk, A. n., Desnick, R. J., Scott, S. A. 2016; 37 (3): 315–23


    The cytochrome P450-2D6 (CYP2D6) enzyme metabolizes ∼25% of common medications, yet homologous pseudogenes and copy number variants (CNVs) make interrogating the polymorphic CYP2D6 gene with short-read sequencing challenging. Therefore, we developed a novel long-read, full gene CYP2D6 single molecule real-time (SMRT) sequencing method using the Pacific Biosciences platform. Long-range PCR and CYP2D6 SMRT sequencing of 10 previously genotyped controls identified expected star (*) alleles, but also enabled suballele resolution, diplotype refinement, and discovery of novel alleles. Coupled with an optimized variant-calling pipeline, CYP2D6 SMRT sequencing was highly reproducible as triplicate intra- and inter-run nonreference genotype results were completely concordant. Importantly, targeted SMRT sequencing of upstream and downstream CYP2D6 gene copies characterized the duplicated allele in 15 control samples with CYP2D6 CNVs. The utility of CYP2D6 SMRT sequencing was further underscored by identifying the diplotypes of 14 samples with discordant or unclear CYP2D6 configurations from previous targeted genotyping, which again included suballele resolution, duplicated allele characterization, and discovery of a novel allele and tandem arrangement. Taken together, long-read CYP2D6 SMRT sequencing is an innovative, reproducible, and validated method for full-gene characterization, duplication allele-specific analysis, and novel allele discovery, which will likely improve CYP2D6 metabolizer phenotype prediction for both research and clinical testing applications.

    View details for DOI 10.1002/humu.22936

    View details for PubMedID 26602992

    View details for PubMedCentralID PMC4752389

  • Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors CLINICAL PHARMACOLOGY & THERAPEUTICS Hicks, J. K., Bishop, J. R., Sangkuhl, K., Mueller, D. J., Ji, Y., Leckband, S. G., Leeder, J. S., GRAHAM, R. L., Chiulli, D. L., Llerena, A., Skaar, T. C., Scott, S. A., Stingl, J. C., Klein, T. E., Caudle, K. E., Gaedigk, A. 2015; 98 (1): 127-134


    Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at

    View details for DOI 10.1002/cpt.147

    View details for Web of Science ID 000358503400005

    View details for PubMedCentralID PMC4512908

  • ClinGen - The Clinical Genome Resource NEW ENGLAND JOURNAL OF MEDICINE Rehm, H. L., Berg, J. S., Brooks, L. D., Bustamante, C. D., Evans, J. P., Landrum, M. J., Ledbetter, D. H., Maglott, D. R., Martin, C. L., Nussbaum, R. L., Plon, S. E., Ramos, E. M., Sherry, S. T., Watson, M. S. 2015; 372 (23): 2235-2242

    View details for DOI 10.1056/NEJMsr1406261

    View details for PubMedID 26014595

  • The pharmacogenetic control of antiplatelet response: candidate genes and CYP2C19. Expert opinion on drug metabolism & toxicology Yang, Y. n., Lewis, J. P., Hulot, J. S., Scott, S. A. 2015; 11 (10): 1599–1617


    Aspirin, clopidogrel, prasugrel and ticagrelor are antiplatelet agents for the prevention of ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) and other indications. Variability in response is observed to different degrees with these agents, which can translate to increased risks for adverse cardiovascular events. As such, potential pharmacogenetic determinants of antiplatelet pharmacokinetics, pharmacodynamics and clinical outcomes have been actively studied.This article provides an overview of the available antiplatelet pharmacogenetics literature. Evidence supporting the significance of candidate genes and their potential influence on antiplatelet response and clinical outcomes are summarized and evaluated. Additional focus is directed at CYP2C19 and clopidogrel response, including the availability of clinical testing and genotype-directed antiplatelet therapy.The reported aspirin response candidate genes have not been adequately replicated and few candidate genes have thus far been implicated in prasugrel or ticagrelor response. However, abundant data support the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients. Although limited prospective trial data are available to support the utility of routine CYP2C19 testing, the increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available.

    View details for DOI 10.1517/17425255.2015.1068757

    View details for PubMedID 26173871

    View details for PubMedCentralID PMC4829114

  • Quantitative and multiplexed DNA methylation analysis using long-read single-molecule real-time bisulfite sequencing (SMRT-BS). BMC genomics Yang, Y. n., Sebra, R. n., Pullman, B. S., Qiao, W. n., Peter, I. n., Desnick, R. J., Geyer, C. R., DeCoteau, J. F., Scott, S. A. 2015; 16: 350


    DNA methylation has essential roles in transcriptional regulation, imprinting, X chromosome inactivation and other cellular processes, and aberrant CpG methylation is directly involved in the pathogenesis of human imprinting disorders and many cancers. To address the need for a quantitative and highly multiplexed bisulfite sequencing method with long read lengths for targeted CpG methylation analysis, we developed single-molecule real-time bisulfite sequencing (SMRT-BS).Optimized bisulfite conversion and PCR conditions enabled the amplification of DNA fragments up to ~1.5 kb, and subjecting overlapping 625-1491 bp amplicons to SMRT-BS indicated high reproducibility across all amplicon lengths (r=0.972) and low standard deviations (≤0.10) between individual CpG sites sequenced in triplicate. Higher variability in CpG methylation quantitation was correlated with reduced sequencing depth, particularly for intermediately methylated regions. SMRT-BS was validated by orthogonal bisulfite-based microarray (r=0.906; 42 CpG sites) and second generation sequencing (r=0.933; 174 CpG sites); however, longer SMRT-BS amplicons (>1.0 kb) had reduced, but very acceptable, correlation with both orthogonal methods (r=0.836-0.897 and r=0.892-0.927, respectively) compared to amplicons less than ~1.0 kb (r=0.940-0.951 and r=0.948-0.963, respectively). Multiplexing utility was assessed by simultaneously subjecting four distinct CpG island amplicons (702-866 bp; 325 CpGs) and 30 hematological malignancy cell lines to SMRT-BS (average depth of 110X), which identified a spectrum of highly quantitative methylation levels across all interrogated CpG sites and cell lines.SMRT-BS is a novel, accurate and cost-effective targeted CpG methylation method that is amenable to a high degree of multiplexing with minimal clonal PCR artifacts. Increased sequencing depth is necessary when interrogating longer amplicons (>1.0 kb) and the previously reported bisulfite sequencing PCR bias towards unmethylated DNA should be considered when measuring intermediately methylated regions. Coupled with an optimized bisulfite PCR protocol, SMRT-BS is capable of interrogating ~1.5 kb amplicons, which theoretically can cover ~91% of CpG islands in the human genome.

    View details for DOI 10.1186/s12864-015-1572-7

    View details for PubMedID 25943404

    View details for PubMedCentralID PMC4422326

  • Design and Anticipated Outcomes of the eMERGE-PGx Project: A Multicenter Pilot for Preemptive Pharmacogenomics in Electronic Health Record Systems CLINICAL PHARMACOLOGY & THERAPEUTICS Rasmussen-Torvik, L. J., Stallings, S. C., Gordon, A. S., Almoguera, B., Basford, M. A., Bielinski, S. J., Brautbar, A., Brilliant, M. H., Carrell, D. S., Connolly, J. J., Crosslin, D. R., Doheny, K. F., Gallego, C. J., Gottesman, O., Kim, D. S., Leppig, K. A., Li, R., Lin, S., Manzi, S., Mejia, A. R., Pacheco, J. A., Pan, V., Pathak, J., Perry, C. L., Peterson, J. F., Prows, C. A., Ralston, J., Rasmussen, L. V., Ritchie, M. D., Sadhasivam, S., Scott, S. A., Smith, M., Vega, A., Vinks, A. A., Volpi, S., Wolf, W. A., Bottinger, E., Chisholm, R. L., Chute, C. G., Haines, J. L., Harley, J. B., Keating, B., Holm, I. A., Kullo, I. J., Jarvik, G. P., Larson, E. B., Manolio, T., McCarty, C. A., Nickerson, D. A., Scherer, S. E., Williams, M. S., Roden, D. M., Denny, J. C. 2014; 96 (4): 482–89


    We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

    View details for DOI 10.1038/clpt.2014.137

    View details for Web of Science ID 000342675400027

    View details for PubMedID 24960519

    View details for PubMedCentralID PMC4169732

  • An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy GENETICS IN MEDICINE Luo, M., Liu, L., Peter, I., Zhu, J., Scott, S. A., Zhao, G., Eversley, C., Kornreich, R., Desnick, R. J., Edelmann, L. 2014; 16 (2): 149–56


    Spinal muscular atrophy is a common autosomal-recessive disorder caused by mutations of the SMN1 gene. Spinal muscular atrophy carrier screening uses dosage-sensitive methods that determine SMN1 copy number, and the frequency of carriers varies by ethnicity, with detection rates ranging from 71 to 94% due to the inability to identify silent (2 + 0) carriers with two copies of SMN1 on one chromosome 5 and deletion on the other. We hypothesized that identification of deletion and/or duplication founder alleles might provide an approach to identify silent carriers in various ethnic groups.SMN1 founder alleles were investigated in the Ashkenazi Jewish population by microsatellite analysis and next-generation sequencing.An extended haplotype block, specific to Ashkenazi Jewish SMN1 duplications, was identified by microsatellite analysis, and next-generation sequencing of SMN1 further defined a more localized haplotype. Of note, six novel SMN1 sequence variants were identified that were specific to duplications and not present on single-copy alleles. The haplotype was also identified on SMN1 duplication alleles in additional ethnic groups.Identification of these novel variants in an individual with two copies of SMN1 significantly improves the accuracy of residual risk estimates and has important implications for spinal muscular atrophy carrier screening.

    View details for DOI 10.1038/gim.2013.84

    View details for Web of Science ID 000331212700004

    View details for PubMedID 23788250

  • Incorporation of Pharmacogenomics into Routine Clinical Practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline Development Process. Current drug metabolism Caudle, K. E., Klein, T. E., Hoffman, J. M., Muller, D. J., Whirl-Carrillo, M., Gong, L., McDonagh, E. M., Sangkuhl, K., Thorn, C. F., Schwab, M., Agundez, J. A., Freimuth, R. R., Huser, V., Lee, M. T., Iwuchukwu, O. F., Crews, K. R., Scott, S. A., Wadelius, M., Swen, J. J., Tyndale, R. F., Stein, C. M., Roden, D., Relling, M. V., Williams, M. S., Johnson, S. G. 2014; 15 (2): 209-217


    The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines.

    View details for PubMedID 24479687

  • Paroxysmal kinesigenic dyskinesia caused by 16p11.2 microdeletion. Tremor and other hyperkinetic movements (New York, N.Y.) Termsarasab, P. n., Yang, A. C., Reiner, J. n., Mei, H. n., Scott, S. A., Frucht, S. J. 2014; 4: 274


    Four cases of paroxysmal kinesigenic dyskinesia (PKD) have been reported in individuals with proximal 16p11.2 microdeletions that include PRRT2.We describe a fifth patient with PKD, features of Asperger's syndrome, and mild language delays. Sanger sequencing of the PRRT2 gene did not identify any mutations implicated in PKD. However, microarray-based comparative genomic hybridization (aCGH) detected a 533.9-kb deletion on chromosome 16, encompassing over 20 genes and transcripts.This case underscores the importance of aCGH testing for individuals with PKD who do not have PRRT2 mutations, particularly when developmental delays, speech problems, intellectual disability, and/or autism spectrum disorder are present.

    View details for DOI 10.7916/D8N58K0Q

    View details for PubMedID 25667815

    View details for PubMedCentralID PMC4303604

  • Physician Attitudes toward Adopting Genome-Guided Prescribing through Clinical Decision Support. Journal of personalized medicine Overby, C. L., Erwin, A. L., Abul-Husn, N. S., Ellis, S. B., Scott, S. A., Obeng, A. O., Kannry, J. L., Hripcsak, G. n., Bottinger, E. P., Gottesman, O. n. 2014; 4 (1): 35–49


    This study assessed physician attitudes toward adopting genome-guided prescribing through clinical decision support (CDS), prior to enlisting in the Clinical Implementation of Personalized Medicine through Electronic Health Records and Genomics pilot pharmacogenomics project (CLIPMERGE PGx). We developed a survey instrument that includes the Evidence Based Practice Attitude Scale, adapted to measure attitudes toward adopting genome-informed interventions (EBPAS-GII). The survey also includes items to measure physicians' characteristics (awareness, experience, and perceived usefulness), attitudes about personal genome testing (PGT) services, and comfort using technology. We surveyed 101 General Internal Medicine physicians from the Icahn School of Medicine at Mount Sinai (ISMMS). The majority were residency program trainees (~88%). Prior to enlisting into CLIPMERGE PGx, most physicians were aware of and had used decision support aids. Few physicians, however, were aware of and had used genome-guided prescribing. The majority of physicians viewed decision support aids and genotype data as being useful for making prescribing decisions. Most physicians had not heard of, but were willing to use, PGT services and felt comfortable interpreting PGT results. Most physicians were comfortable with technology. Physicians who perceived genotype data to be useful in making prescribing decisions, had more positive attitudes toward adopting genome-guided prescribing through CDS. Our findings suggest that internal medicine physicians have a deficit in their familiarity and comfort interpreting and using genomic information. This has reinforced the importance of gathering feedback and guidance from our enrolled physicians when designing genome-guided CDS and the importance of prioritizing genomic medicine education at our institutions.

    View details for DOI 10.3390/jpm4010035

    View details for PubMedID 25562141

    View details for PubMedCentralID PMC4251406

  • Implementation and utilization of genetic testing in personalized medicine. Pharmacogenomics and personalized medicine Abul-Husn, N. S., Owusu Obeng, A. n., Sanderson, S. C., Gottesman, O. n., Scott, S. A. 2014; 7: 227–40


    Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient's clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing.

    View details for DOI 10.2147/PGPM.S48887

    View details for PubMedID 25206309

    View details for PubMedCentralID PMC4157398

  • Warfarin pharmacogenetic trials: is there a future for pharmacogenetic-guided dosing? Pharmacogenomics Scott, S. A., Lubitz, S. A. 2014; 15 (6): 719–22

    View details for DOI 10.2217/pgs.14.18

    View details for PubMedID 24897277

    View details for PubMedCentralID PMC4110075

  • Antiplatelet drug interactions with proton pump inhibitors. Expert opinion on drug metabolism & toxicology Scott, S. A., Owusu Obeng, A. n., Hulot, J. S. 2014; 10 (2): 175–89


    Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent.This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated.Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers.

    View details for DOI 10.1517/17425255.2014.856883

    View details for PubMedID 24205916

    View details for PubMedCentralID PMC4110685

  • Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation PHARMACOGENOMICS JOURNAL Martis, S., Mei, H., Vijzelaar, R., Edelmann, L., Desnick, R. J., Scott, S. A. 2013; 13 (6): 558–66


    To determine the role of CYP450 copy number variation (CNV) beyond CYP2D6, 11 CYP450 genes were interrogated by multiplex ligation-dependent probe amplification and quantitative PCR in 542 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals. The CYP2A6, CYP2B6 and CYP2E1 combined deletion/duplication allele frequencies ranged from 2 to 10% in these populations. High-resolution microarray-based comparative genomic hybridization (aCGH) localized CYP2A6, CYP2B6 and CYP2E1 breakpoints to directly oriented low-copy repeats. Sequencing localized the CYP2B6 breakpoint to a 529-bp intron 4 region with high homology to CYP2B7P1, resulting in the CYP2B6*29 partial deletion allele and the reciprocal, and novel, CYP2B6/2B7P1 duplicated fusion allele (CYP2B6*30). Together, these data identified novel CYP450 CNV alleles (CYP2B6*30 and CYP2E1*1Cx2) and indicate that common CYP450 CNV formation is likely mediated by non-allelic homologous recombination resulting in both full gene and gene-fusion copy number imbalances. Detection of these CNVs should be considered when interrogating these genes for pharmacogenetic drug selection and dosing.

    View details for DOI 10.1038/tpj.2012.48

    View details for Web of Science ID 000327449700012

    View details for PubMedID 23164804

    View details for PubMedCentralID PMC3580117

  • The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future GENETICS IN MEDICINE Gottesman, O., Kuivaniemi, H., Tromp, G., Faucett, W., Li, R., Manolio, T. A., Sanderson, S. C., Kannry, J., Zinberg, R., Basford, M. A., Brilliant, M., Carey, D. J., Chisholm, R. L., Chute, C. G., Connolly, J. J., Crosslin, D., Denny, J. C., Gallego, C. J., Haines, J. L., Hakonarson, H., Harley, J., Jarvik, G. P., Kohane, I., Kullo, I. J., Larson, E. B., McCarty, C., Ritchie, M. D., Roden, D. M., Smith, M. E., Bottinger, E. P., Williams, M. S., eMerge Network 2013; 15 (10): 761–71


    The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute-funded consortium engaged in the development of methods and best practices for using the electronic medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine.

    View details for DOI 10.1038/gim.2013.72

    View details for Web of Science ID 000325665000002

    View details for PubMedID 23743551

    View details for PubMedCentralID PMC3795928

  • Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update CLINICAL PHARMACOLOGY & THERAPEUTICS Scott, S. A., Sangkuhl, K., Stein, C. M., Hulot, J., Mega, J. L., Roden, D. M., Klein, T. E., Sabatine, M. S., Johnson, J. A., Shuldiner, A. R. 2013; 94 (3): 317-323

    View details for DOI 10.1038/clpt.2013.105

    View details for Web of Science ID 000323686900016

    View details for PubMedID 23698643

  • Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet Perera, M. A., Cavallari, L. H., Limdi, N. A., Gamazon, E. R., Konkashbaev, A., Daneshjou, R., Pluzhnikov, A., Crawford, D. C., Wang, J., Liu, N., Tatonetti, N., Bourgeois, S., Takahashi, H., Bradford, Y., Burkley, B. M., Desnick, R. J., Halperin, J. L., Khalifa, S. I., Langaee, T. Y., Lubitz, S. A., Nutescu, E. A., Oetjens, M., Shahin, M. H., Patel, S. R., Sagreiya, H., Tector, M., Weck, K. E., Rieder, M. J., Scott, S. A., Wu, A. H., Burmester, J. K., Wadelius, M., Deloukas, P., Wagner, M. J., Mushiroda, T., Kubo, M., Roden, D. M., Cox, N. J., Altman, R. B., Klein, T. E., Nakamura, Y., Johnson, J. A. 2013; 382 (9894): 790-796


    BACKGROUND: VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. METHODS: We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. FINDINGS: The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). INTERPRETATION: A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. FUNDING: National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust.

    View details for DOI 10.1016/S0140-6736(13)60681-9

    View details for PubMedID 23755828

  • Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes PHARMACOGENOMICS JOURNAL Martis, S., Peter, I., Hulot, J., Kornreich, R., Desnick, R. J., Scott, S. A. 2013; 13 (4): 369–77


    To determine CYP2C19 and CYP2C8 allele frequencies, 28 coding and/or functional variants were genotyped in 1250 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) individuals. The combined CYP2C19 variant allele frequencies ranged from ∼0.30 to 0.41; however, the CYP2C8 frequencies were much lower (∼0.04-0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies >0.5%. Notably, the 2C19*17-2C9*1-2C8*2 haplotype was identified among African-Americans (8%) and Hispanics (2%), indicating that CYP2C19*17 does not always tag a CYP2C haplotype that encodes efficient CYP2C-substrate metabolism. The 2C19*1-2C9*2-2C8*3 haplotype was identified in all populations except African-Americans and additional novel haplotypes were identified in selected populations (for example, 2C19*2-2C9*1-2C8*4 and 2C19*4B-2C9*1-2C8*1), together indicating that both CYP2C19*17 and *2 can be linked with other CYP2C loss-of-function alleles. These results have important implications for pharmacogenomic association studies involving the CYP2C locus and are clinically relevant when administering CYP2C-substrate medications.

    View details for DOI 10.1038/tpj.2012.10

    View details for Web of Science ID 000322524900013

    View details for PubMedID 22491019

    View details for PubMedCentralID PMC3396745

  • The CLIPMERGE PGx Program: Clinical Implementation of Personalized Medicine Through Electronic Health Records and Genomics-Pharmacogenomics CLINICAL PHARMACOLOGY & THERAPEUTICS Gottesman, O., Scott, S. A., Ellis, S. B., Overby, C. L., Ludtke, A., Hulot, J., Hall, J., Chatani, K., Myers, K., Kannry, J. L., Bottinger, E. P. 2013; 94 (2): 214–17

    View details for DOI 10.1038/clpt.2013.72

    View details for Web of Science ID 000322064400020

    View details for PubMedID 23588317

    View details for PubMedCentralID PMC3720762

  • Combined and independent impact of diabetes mellitus and chronic kidney disease on residual platelet reactivity THROMBOSIS AND HAEMOSTASIS Baber, U., Bander, J., Karajgikar, R., Yadav, K., Hadi, A., Theodoropolous, K., Gukathasan, N., Roy, S., Sayeneni, S., Scott, S. A., Kovacic, J. C., Yu, J., Sartori, S., Mehran, R., Uribarri, J., Badimon, J. J., Muntner, P., Moreno, P., Kini, A. S., Sharma, S. K. 2013; 110 (1): 118–23


    Patients with both chronic kidney disease (CKD) and diabetes mellitus (DM) are at increased risk for thrombotic events compared to those with one abnormality alone. Whether this can be attributed to changes in platelet reactivity among those with both CKD and DM is unknown. We prospectively studied 438 clopidogrel-naïve patients undergoing percutaneous coronary intervention (PCI). Platelet function tests were performed 4-6 hours after loading with 600 mg of clopidogrel. Platelet reactivity was assessed using the VerifyNow system and expressed as P2Y12 reaction units (PRU). High residual platelet reactivity (HRPR) was defined as PRU > 230. Patients were categorised into four groups by the presence or absence of CKD and DM. Among those without CKD or DM (n=166), DM alone (n=150), CKD alone (n=60) and both CKD and DM (n=62) the mean PRU levels were 201.6 ± 96.3, 220.5 ± 101.1, 254.9 ± 106.7 and 275.0 ± 94.5, respectively (p<0.001). Analogously, the prevalence of HRPR was 42.3%, 50.7%, 63.3% and 75.8%, respectively (p< 0.001). Associations between either CKD or DM alone and HRPR were attenuated after multivariable adjustment while the odds for HRPR associated with both CKD and DM remained significant (OR [95% CI]: 2.61 [1.16 - 5.86]). In conclusion, the presence of both CKD and DM confers a synergistic impact on residual platelet reactivity when compared to either condition alone. Whether more potent platelet inhibitors may improve outcomes among patients with both abnormalities warrants investigation.

    View details for DOI 10.1160/TH13-01-0004

    View details for Web of Science ID 000321475800018

    View details for PubMedID 23677380

  • Warfarin pharmacogenetics: a controlled dose-response study in healthy subjects. Vascular medicine (London, England) Kadian-Dodov, D. L., van der Zee, S. A., Scott, S. A., Peter, I. n., Martis, S. n., Doheny, D. O., Rothlauf, E. B., Lubitz, S. A., Desnick, R. J., Halperin, J. L. 2013; 18 (5): 290–97


    The aim of this study was to determine how genetic variants contribute to warfarin dosing variability when non-genetic factors are controlled. Thirty healthy subjects were subjected to a warfarin dosing algorithm with daily international normalized ratio (INR) measurements to INR ≥ 2.0, then off warfarin to INR ≤ 1.2. The primary outcome was the cumulative dose required to achieve INR ≥ 2.0 for 2 consecutive days. CYP2C9 (p=0.004) and VKORC1 (p=0.02) variant carriers required lower cumulative doses, and CYP4F2 carriers required higher doses (p=0.04). Subjects with variants in both CYP2C9 and VKORC1 required fewer days to reach INR ≥ 2.0 than wild-type subjects or those with variants in CYP2C9 or VKORC1 (p=0.01). Genetic contribution to dose variability (~62%) was greater than previously reported, suggesting that uncontrolled clinical variables influence the effect of these variants. In conclusion, genotype-guided warfarin-dosing algorithms may rely more on genetic variables in healthier individuals than in patients with clinical confounders.

    View details for DOI 10.1177/1358863X13503193

    View details for PubMedID 24029542

  • Clinical Pharmacogenomics: Opportunities and Challenges at Point of Care CLINICAL PHARMACOLOGY & THERAPEUTICS Scott, S. A. 2013; 93 (1): 33–35

    View details for DOI 10.1038/clpt.2012.196

    View details for Web of Science ID 000312618200022

    View details for PubMedID 23212102

    View details for PubMedCentralID PMC3576863

  • An allele-specific PCR system for rapid detection and discrimination of the CYP2C19∗4A, ∗4B, and ∗17 alleles: implications for clopidogrel response testing. The Journal of molecular diagnostics : JMD Scott, S. A., Tan, Q. n., Baber, U. n., Yang, Y. n., Martis, S. n., Bander, J. n., Kornreich, R. n., Hulot, J. S., Desnick, R. J. 2013; 15 (6): 783–89


    CYP2C19 is involved in the metabolism of clinically relevant drugs, including the antiplatelet prodrug clopidogrel, which has prompted interest in clinical CYP2C19 genotyping. The CYP2C19∗4B allele is defined by both gain-of-function [c.-806C>T (∗17)] and loss-of-function [c.1A>G (∗4)] variants on the same haplotype; however, current genotyping and sequencing assays are unable to determine the phase of these variants. Thus, the aim of this study was to develop an assay that could rapidly detect and discriminate the related ∗4A, ∗4B, and ∗17 alleles. An allele-specific PCR assay, composed of four unique primer mixes that specifically interrogate the defining ∗17 and ∗4 variants, was developed by using samples (n = 20) with known genotypes, including the ∗4A, ∗4B, and/or ∗17 alleles. The assay was validated by testing 135 blinded samples, and the results were correlated with CYP2C19 genotyping and allele-specific cloning/sequencing. Importantly, among the six ∗4 carriers in the validation cohort, after allele-specific PCR testing both samples with a ∗1/∗4 genotype were reclassified to ∗1/∗4A, all three samples with a ∗4/∗17 genotype were reclassified to ∗1/∗4B, and a sample with a ∗4/∗17/∗17 genotype was reclassified to ∗4B/∗17. In conclusion, this rapid and robust allele-specific PCR assay can refine CYP2C19 genotyping and metabolizer phenotype classification by determining the phase of the defining ∗17 and ∗4 variants, which may have utility when testing CYP2C19 for clopidogrel response.

    View details for DOI 10.1016/j.jmoldx.2013.06.004

    View details for PubMedID 24012947

  • Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology (Baltimore, Md.) Scott, S. A., Liu, B. n., Nazarenko, I. n., Martis, S. n., Kozlitina, J. n., Yang, Y. n., Ramirez, C. n., Kasai, Y. n., Hyatt, T. n., Peter, I. n., Desnick, R. J. 2013; 58 (3): 958–65


    Cholesteryl ester storage disease (CESD) and Wolman disease are autosomal recessive later-onset and severe infantile disorders, respectively, which result from the deficient activity of lysosomal acid lipase (LAL). LAL is encoded by LIPA (10q23.31) and the most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; E8SJM), which expresses only ∼3%-5% of normally spliced LAL. However, the frequency of c.894G>A is unknown in most populations. To estimate the prevalence of CESD in different populations, the frequencies of the c.894G>A mutation were determined in 10,000 LIPA alleles from healthy African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals from the greater New York metropolitan area and 6,578 LIPA alleles from African-American, Caucasian, and Hispanic subjects enrolled in the Dallas Heart Study. The combined c.894G>A allele frequencies from the two cohorts ranged from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of 1 in 1,000 to ∼1 in 300, respectively. No African-American heterozygotes were detected. Additionally, by surveying the available literature, c.894G>A was estimated to account for 60% (95% confidence interval [CI]: 51%-69%) of reported mutations among multiethnic CESD patients. Using this estimate, the predicted prevalence of CESD in the Caucasian and Hispanic populations is ∼0.8 per 100,000 (∼1 in 130,000; 95% CI: ∼1 in 90,000 to 1 in 170,000).These data indicate that CESD may be underdiagnosed in the general Caucasian and Hispanic populations, which is important since clinical trials of enzyme replacement therapy for LAL deficiency are currently being developed. Moreover, future studies on CESD prevalence in African and Asian populations may require full-gene LIPA sequencing to determine heterozygote frequencies, since c.894G>A is not common in these racial groups.

    View details for DOI 10.1002/hep.26327

    View details for PubMedID 23424026

    View details for PubMedCentralID PMC3690149

  • Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis CLINICAL PHARMACOLOGY & THERAPEUTICS Danese, E., Montagnana, M., Johnson, J. A., Rettie, A. E., Zambon, C. F., Lubitz, S. A., Suarez-Kurtz, G., Cavallari, L. H., Zhao, L., Huang, M., Nakamura, Y., Mushiroda, T., Kringen, M. K., Borgiani, P., Ciccacci, C., Au, N. T., Langaee, T., Siguret, V., Loriot, M. A., Sagreiya, H., Altman, R. B., Shahin, M. H., Scott, S. A., Khalifa, S. I., Chowbay, B., Suriapranata, I. M., Teichert, M., Stricker, B. H., Taljaard, M., Botton, M. R., Zhang, J. E., Pirmohamed, M., Zhang, X., Carlquist, J. F., Horne, B. D., Lee, M. T., Pengo, V., Guidi, G. C., Minuz, P., Fava, C. 2012; 92 (6): 746-756


    A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I(2) = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.

    View details for DOI 10.1038/clpt.2012.184

    View details for Web of Science ID 000311283400016

    View details for PubMedID 23132553

  • Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness PHARMACOGENOMICS JOURNAL Scott, S. A., Martis, S., Peter, I., Kasai, Y., Kornreich, R., Desnick, R. J. 2012; 12 (4): 297–305


    CYP2C19 is a principal enzyme involved in the bioactivation of the antiplatelet prodrug clopidogrel and common CYP2C19 loss-of-function alleles are associated with adverse cardiovascular events. To assess the impact of the CYP2C19*17 increased activity allele in the Ashkenazi Jewish (AJ) and Sephardi Jewish (SJ) populations and to determine the frequencies of additional variant alleles, 250 AJ and 135 SJ individuals were genotyped for CYP2C19*2-*10, *12-*17, *22 and P-glycoprotein (ABCB1) c.3435C>T. Importantly, CYP2C19*4, a loss-of-function allele, was identified in linkage disequilibrium with *17. This novel haplotype, designated CYP2C19*4B, significantly alters the interpretation of CYP2C19 genotyping when testing *17. Moreover, genotyping CYP2C19*17 changed the frequency of extensive metabolizers from ∼70 to ∼40%, reclassifying ∼30% as ultrarapid metabolizers. Combining CYP2C19 and ABCB1 identified ∼1 in 3 AJ and ∼1 in 2 SJ individuals at increased risk for adverse responses to clopidogrel. These data underscore the importance of including *4B and *17 when clinically genotyping CYP2C19.

    View details for DOI 10.1038/tpj.2011.5

    View details for Web of Science ID 000306944300003

    View details for PubMedID 21358751

    View details for PubMedCentralID PMC3310336

  • Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU PHARMACOGENOMICS Scott, S. A., Patel, M., Martis, S., Lubitz, S. A., van der Zee, S., Yoo, C., Edelmann, L., Halperin, J. L., Desnick, R. J. 2012; 13 (3): 297–307


    To determine if copy number variants contribute to warfarin dose requirements, we investigated CYP2C9, VKORC1, CYP4F2, GGCX and CALU for deletions and duplications in a multiethnic patient population treated with therapeutic doses of warfarin.DNA samples from 178 patients were subjected to copy number analyses by multiplex ligation-dependent probe amplification or quantitative PCR assays. Additionally, the CYP2C9 exon 8 insertion/deletion polymorphism (rs71668942) was examined among the patient cohort and 1750 additional multiethnic healthy individuals.All patients carried two copies of CYP2C9 by multiplex ligation-dependent probe amplification and no exon 8 deletion carriers were detected. Similarly, quantitative PCR assays for VKORC1, CYP4F2, GGCX and CALU identified two copies in all populations.These data indicate that copy number variants in the principal genes involved in warfarin dose variability (CYP2C9, VKORC1), including genes with lesser effect (CYP4F2, GGCX), and those that may be more relevant among certain racial groups (CALU), are rare in multiethnic populations, including African-Americans.

    View details for DOI 10.2217/PGS.11.156

    View details for Web of Science ID 000301886500015

    View details for PubMedID 22188360

    View details for PubMedCentralID PMC3292047

  • PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19 PHARMACOGENETICS AND GENOMICS Scott, S. A., Sangkuhl, K., Shuldiner, A. R., Hulot, J., Thorn, C. F., Altman, R. B., Klein, T. E. 2012; 22 (2): 159-165

    View details for DOI 10.1097/FPC.0b013e32834d4962

    View details for Web of Science ID 000299310600008

    View details for PubMedID 22027650

    View details for PubMedCentralID PMC3349992

  • Personalizing medicine with clinical pharmacogenetics GENETICS IN MEDICINE Scott, S. A. 2011; 13 (12): 987–95


    Clinical genetic testing has grown substantially over the past 30 years as the causative mutations for Mendelian diseases have been identified, particularly aided in part by the recent advances in molecular-based technologies. Importantly, the adoption of new tests and testing strategies (e.g., diagnostic confirmation, prenatal testing, and population-based carrier screening) has often been met with caution and careful consideration before clinical implementation, which facilitates the appropriate use of new genetic tests. Although the field of pharmacogenetics was established in the 1950s, clinical testing for constitutional pharmacogenetic variants implicated in interindividual drug response variability has only recently become available to help clinicians guide pharmacotherapy, in part due to US Food and Drug Administration-mediated product insert revisions that include pharmacogenetic information for selected drugs. However, despite pharmacogenetic associations with adverse outcomes, physician uptake of clinical pharmacogenetic testing has been slow. Compared with testing for Mendelian diseases, pharmacogenetic testing for certain indications can have a lower positive predictive value, which is one reason for underutilization. A number of other barriers remain with implementing clinical pharmacogenetics, including clinical utility, professional education, and regulatory and reimbursement issues, among others. This review presents some of the current opportunities and challenges with implementing clinical pharmacogenetic testing.

    View details for DOI 10.1097/GIM.0b013e318238b38c

    View details for Web of Science ID 000298138700001

    View details for PubMedID 22095251

    View details for PubMedCentralID PMC3290900

  • Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing CLINICAL PHARMACOLOGY & THERAPEUTICS Johnson, J. A., Gong, L., Whirl-Carrillo, M., Gage, B. F., Scott, S. A., Stein, C. M., Anderson, J. L., Kimmel, S. E., Lee, M. T., Pirmohamed, M., Wadelius, M., Klein, T. E., Altman, R. B. 2011; 90 (4): 625-629


    Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on based on new developments in the field.(1).

    View details for DOI 10.1038/clpt.2011.185

    View details for Web of Science ID 000295119200035

    View details for PubMedID 21900891

    View details for PubMedCentralID PMC3187550

  • Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450-2C19 (CYP2C19) Genotype and Clopidogrel Therapy CLINICAL PHARMACOLOGY & THERAPEUTICS Scott, S. A., Sangkuhl, K., Gardner, E. E., Stein, C. M., Hulot, J., Johnson, J. A., Roden, D. M., Klein, T. E., Shuldiner, A. R. 2011; 90 (2): 328-332

    View details for DOI 10.1038/clpt.2011.132

    View details for Web of Science ID 000292974900028

    View details for PubMedID 21716271

    View details for PubMedCentralID PMC3234301

  • Experience with Carrier Screening and Prenatal Diagnosis for 16 Ashkenazi Jewish Genetic Diseases HUMAN MUTATION Scott, S. A., Edelmann, L., Liu, L., Luo, M., Desnick, R. J., Kornreich, R. 2010; 31 (11): 1240–50


    The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease-causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ-descended individuals, screening for 16 disorders resulted in ∼1 in 3.3 being a carrier for one disease and ∼1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ∼15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease-causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population.

    View details for DOI 10.1002/humu.21327

    View details for Web of Science ID 000283783600015

    View details for PubMedID 20672374

    View details for PubMedCentralID PMC2970726

  • Large inverted repeats within Xp11.2 are present at the breakpoints of isodicentric X chromosomes in Turner syndrome HUMAN MOLECULAR GENETICS Scott, S. A., Cohen, N., Brandt, T., Warburton, P. E., Edelmann, L. 2010; 19 (17): 3383–93


    Turner syndrome (TS) results from whole or partial monosomy X and is mediated by haploinsufficiency of genes that normally escape X-inactivation. Although a 45,X karyotype is observed in half of all TS cases, the most frequent variant TS karyotype includes the isodicentric X chromosome alone [46,X,idic(X)(p11)] or as a mosaic [46,X,idic(X)(p11)/45,X]. Given the mechanism of idic(X)(p11) rearrangement is poorly understood and breakpoint sequence information is unknown, this study sought to investigate the molecular mechanism of idic(X)(p11) formation by determining their precise breakpoint intervals. Karyotype analysis and fluorescence in situ hybridization mapping of eight idic(X)(p11) cell lines and three unbalanced Xp11.2 translocation lines identified the majority of breakpoints within a 5 Mb region, from approximately 53 to 58 Mb, in Xp11.1-p11.22, clustering into four regions. To further refine the breakpoints, a high-resolution oligonucleotide microarray (average of approximately 350 bp) was designed and array-based comparative genomic hybridization (aCGH) was performed on all 11 idic(X)(p11) and Xp11.2 translocation lines. aCGH analyses identified all breakpoint regions, including an idic(X)(p11) line with two potential breakpoints, one breakpoint shared between two idic(X)(p11) lines and two Xp translocations that shared breakpoints with idic(X)(p11) lines. Four of the breakpoint regions included large inverted repeats composed of repetitive gene clusters and segmental duplications, which corresponded to regions of copy-number variation. These data indicate that the rearrangement sites on Xp11.2 that lead to isodicentric chromosome formation and translocations are probably not random and suggest that the complex repetitive architecture of this region predisposes it to rearrangements, some of which are recurrent.

    View details for DOI 10.1093/hmg/ddq250

    View details for Web of Science ID 000280704800008

    View details for PubMedID 20570968

    View details for PubMedCentralID PMC2916707

  • Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups PHARMACOGENOMICS Scott, S. A., Khasawneh, R., Peter, I., Kornreich, R., Desnick, R. J. 2010; 11 (6): 781–91


    CYP4F2*3 (p.V433M) has been associated with higher warfarin dose requirements; however, its frequency, like other CYP2C9 and VKORC1 variants, has not been systematically assessed in major racial/ethnic populations. Thus, we determined the individual and combined frequencies of important CYP2C9, VKORC1 and CYP4F2 variants in several racial/ethnic groups.Healthy African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) blood donors were genotyped for CYP2C9 (*2, *3, *4, *5, *6, *8, *11 and *13), VKORC1 (g.-1639G>A) and CYP4F2 (*3 [p.V433M] and rs2189784).The combined frequencies of variant CYP2C9 alleles were 0.133, 0.078, 0.212, 0.178 and 0.212 among African-American, Asian, Caucasian, Hispanic and AJ individuals, respectively. CYP4F2*3 frequencies were prevalent (0.233-0.342) among Asian, Caucasian, Hispanic and AJ individuals, while significantly less frequent among African-Americans (0.117; p < 0.0001). In addition, CYP4F2*3 was in linkage disequilibrium with rs2189784, an allele recently associated with time-to-therapeutic international normalized ratio, among all studied populations. Importantly, 87-95% of Asian, Caucasian, Hispanic and AJ individuals had a variant CYP2C9, VKORC1 and/or CYP4F2*3 allele, compared with only 53% of African-Americans (p < 0.0001).Compared with other racial/ethnic populations studied, only approximately one in 80 African-Americans were CYP4F2*3 homozygous, indicating that this population would benefit less from dosing algorithms that include this variant. In addition, the unique allele frequency profiles identified among the different populations partly explain why genotype-guided warfarin dosing algorithms perform less well for African-Americans and suggest that other unidentified genetic and/or nongenetic factors that influence warfarin dosage may exist in this population.

    View details for DOI 10.2217/PGS.10.49

    View details for Web of Science ID 000278605900013

    View details for PubMedID 20504253

    View details for PubMedCentralID PMC2904527

  • Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population JOURNAL OF THROMBOSIS AND HAEMOSTASIS Lubitz, S. A., Scott, S. A., Rothlauf, E. B., Agarwal, A., Peter, I., Doheny, D., van der Zee, S., Jaremko, M., Yoo, C., Desnick, R. J., Halperin, J. L. 2010; 8 (5): 1018–26


    Gene-based warfarin dosing algorithms have largely been developed in homogeneous populations, and their generalizability has not been established.We sought to assess the performance of published algorithms in a racially diverse and multiethnic sample, and determine if additional clinical variables or genetic variants associated with dose could enhance algorithm performance.In 145 compliant patients on warfarin with a goal international normalized ratio (INR) of 2-3, stable, therapeutic doses were compared with predicted doses using 12 reported algorithms that incorporated CYP2C9 and VKORC1 variants. Additional covariates tested with each model included race, concurrent medications, medications known to interact with warfarin and previously described CYP4F2, CALU and GGCX variants.The mean patient age was 67 +/- 14 years; 90 (62%) were male. Eighty-two (57%) were Caucasian, 28 (19%) African-American, 20 (14%) Hispanic and 15 (10%) Asian. The median warfarin dose was 35 mg per week (interquartile range 23-53 mg per week). Gene-based dosing algorithms explained 37-55% of the variation in warfarin dose requirements. Neither the addition of race, number of concurrent medications nor the number of concurrent medications interacting with warfarin enhanced algorithm performance. Similarly, consideration of CYP4F2, CALU or GGCX variant genotypes did not improve algorithms.Existing gene-based dosing algorithms explained between approximately one-third and one-half of the variability in warfarin dose requirements in this racially and ethnically diverse cohort. Additional clinical and recently described genetic variants associated with warfarin dose did not enhance prediction in our patient population.

    View details for DOI 10.1111/j.1538-7836.2010.03792.x

    View details for Web of Science ID 000277328600020

    View details for PubMedID 20128861

    View details for PubMedCentralID PMC4441275

  • Detection of low-level mosaicism and placental mosaicism by oligonucleotide array comparative genomic hybridization GENETICS IN MEDICINE Scott, S. A., Cohen, N., Brandt, T., Toruner, G., Desnick, R. J., Edelmann, L. 2010; 12 (2): 85–92


    To determine the sensitivity of whole-genome oligonucleotide array comparative genomic hybridization for the detection of mosaic cytogenetic abnormalities.Mosaicism sensitivity was evaluated by testing artificially derived whole chromosome and segmental aneuploidies ranging from 0% to 100% abnormal and additional naturally occurring mosaic specimens.Using combined dye-reversed replicates and an unfiltered analysis, oligonucleotide array comparative genomic hybridization detected as low as 10% and 20-30% mosaicism from whole chromosome and segmental aneuploidies, respectively. To investigate discrepancies between cultured and uncultured specimens, array comparative genomic hybridization was performed on DNA from additional direct product of conception specimens with abnormal karyotypes in culture. Interestingly, 5 of 10 product of conception specimens with double trisomies on cultured cell analysis had only a single trisomy by array comparative genomic hybridization and quantitative polymerase chain reaction on DNA from the uncultured direct specimen, and all harbored the more commonly observed trisomy. Thus, oligonucleotide array comparative genomic hybridization revealed previously unidentified placental mosaicism in half of the products of conception with double-aneuploid conventional karyotypes.Oligonucleotide array comparative genomic hybridization can detect low-level mosaicism for whole chromosome ( approximately 10%) and segmental ( approximately 20-30%) aneuploidies when using specific detection criteria. In addition, careful interpretation is required when performing array comparative genomic hybridization on DNA isolated from direct specimens as the results may differ from the cultured chromosome analysis.

    View details for DOI 10.1097/GIM.0b013e3181cc75d0

    View details for Web of Science ID 000275265100004

    View details for PubMedID 20084009

  • Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition ONCOGENE Lakshmikuttyamma, A., Scott, S. A., DeCoteau, J. F., Geyer, C. R. 2010; 29 (4): 576–88


    Reexpression of hypermethylated tumor suppressor genes using DNA methyltransferase (DNMT) and histone deacetylase inhibitors occurs by a mechanism whereby promoter demethylation is the dominant event. In support of this model, we found in acute myeloid leukemia cells with hypermethylated p15INK4B and E-cadherin promoters that the DNMT inhibitor, 5-aza-2'-deoxycytidine, induced p15INK4B and E-cadherin expression, and decreased levels of DNA methylation, histone H3 lysine 9 (H3K9) methylation and SUV39H1 associated with p15INK4B and E-cadherin promoters. On the basis of these observations, we examined whether promoter demethylation was dominant to H3K9 demethylation in p15INK4B and E-cadherin reexpression. We observed that SUV39H1 short hairpin RNA and chaetocin, a SUV39H1 inhibitor, induced p15INK4B and E-cadherin expression and H3K9 demethylation without promoter demethylation. Reexpression of hypermethylated p15INK4B and E-cadherin required histone H3K9 demethylation that was achieved directly by inhibiting SUV39H1 expression or activity, or indirectly by decreasing the amount of SUV39H1 associated with the p15INK4B and E-cadherin promoters using 5-aza-2'-deoxycytidine. The results from this study highlight the potential of H3K9 methyltransferases as therapeutic targets for reactivating expression of hypermethylated genes.

    View details for DOI 10.1038/onc.2009.361

    View details for Web of Science ID 000274084600010

    View details for PubMedID 19881540

  • CYP2C9*8 is prevalent among African-Americans: implications for pharmacogenetic dosing PHARMACOGENOMICS Scott, S. A., Jaremko, M., Lubitz, S. A., Kornreich, R., Halperin, J. L., Desnick, R. J. 2009; 10 (8): 1243–55


    Although the frequencies of pharmacogenetic variants differ among racial groups, most pharmacogenetic algorithms for genotype-guided warfarin dosing only include two CYP2C9 alleles (*2 and *3) and a single VKORC1 allele (g.-1639G>A or g.1173C>T) commonly found among Caucasians. Therefore, this study sought to identify other CYP2C9 and VKORC1 alleles important in warfarin dose variability and to determine their frequencies in different racial and ethnic groups.The CYP2C9 and VKORC1 genes were sequenced in selected sensitive (< 21 mg/week) and resistant (> 49 mg/week) individuals with discrepant therapeutic and algorithm-predicted warfarin doses based on prior CYP2C9 and VKORC1 genotyping. The CYP2C9 and VKORC1 allele frequencies were determined in healthy, racially self-identified blood donors.Sequencing identified an African-American male with a lower than predicted therapeutic warfarin dose (14.4 mg/week), previously genotyped as CYP2C9*1/*1, who was homozygous for CYP2C9*8 (c.449G>A; p.R150H). Genotyping 600 African-American alleles identified CYP2C9*8 as their most frequent variant CYP2C9 allele (0.047), and the combined allele frequency of CYP2C9*2, *3, *5, *6, *8 and *11 was 0.133. Given most warfarin pharmacogenetic dosing algorithms only include CYP2C9*2 and *3, the inclusion of CYP2C9*8 alone could reclassify the predicted metabolic phenotypes of almost 10% of African-Americans, or when combined with CYP2C9*5, *6 and *11, more than 15%. In addition, the African-American VKORC1 g.-1639A allele frequency was 0.108 and three g.1331G>A (p.V66M) carriers were identified.CYP2C9*8 is prevalent among African-Americans ( approximately 1 in 11 individuals). Thus, in this racial group, the incorporation of CYP2C9*8 into genotyping panels may improve dose prediction of CYP2C9-metabolized drugs, including warfarin.

    View details for DOI 10.2217/PGS.09.71

    View details for Web of Science ID 000269408100012

    View details for PubMedID 19663669

    View details for PubMedCentralID PMC2737687

  • Strategies to Re-Express Epigenetically-Silenced Tumor Suppressor Genes Converge on the Requirement for Inhibition of the Histone Methyltransferase SUV39H1 Lakshmikuttyamma, A., Scott, S., Sheridan, D. P., DeCoteau, J., Geyer, R. AMER SOC HEMATOLOGY. 2008: 1152–53
  • Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations AMERICAN JOURNAL OF HUMAN GENETICS Scott, S. A., Edelmann, L., Kornreich, R., Desnick, R. J. 2008; 82 (2): 495–500


    Warfarin is a widely used anticoagulant that has a narrow therapeutic range because of both genetic and environmental factors. CYP2C9( *)2 (p.R144C), CYP2C9( *)3 (p.I359L), and the VKORC1 promoter (g.-1639G-->A) polymorphisms occur frequently in patients who are warfarin "sensitive" and require lower doses, whereas patients with VKORC1 missense mutations are warfarin "resistant" and require higher doses. To compare the CYP2C9 and VKORC1 allele and genotype frequencies among 260 Ashkenazi (AJ) and 80 Sephardi Jewish (SJ) individuals, we genotyped six CYP2C9 and eight VKORC1 alleles by using the Tag-It Mutation Detection Kit and PCR-RFLP assays. The "sensitive"CYP2C9( *)2 and ( *)3 alleles had significantly higher frequencies in SJ than in AJ individuals, 0.194 and 0.144 versus 0.127 and 0.081, respectively (p A, underscoring the importance of screening for p.D36Y prior to initiating warfarin anticoagulation in AJ individuals. Taken together, our findings show that approximately 85% of AJ and approximately 90% of SJ individuals have at least one "sensitive" (CYP2C9( *)2, ( *)3, VKORC1 g.-1639G-->A) or "resistant" (VKORC1 p.D36Y) allele, indicating that each group has different warfarin pharmacogenetics and would benefit from genotype-based dose predictions.

    View details for DOI 10.1016/j.ajhg.2007.10.002

    View details for Web of Science ID 000253223900021

    View details for PubMedID 18252229

    View details for PubMedCentralID PMC2427171

  • Induction of ID1 expression and apoptosis by the histone deacetylase inhibitor (trichostatin A) in human acute myeloid leukaemic cells CELL PROLIFERATION Yu, W., Scott, S. A., Dong, W. 2008; 41 (1): 86–97


    ID1, founding member of the inhibitor of differentiation (ID) family, is involved in cell population growth, apoptosis and tumourigenesis.We investigated mRNA levels of ID1 in human myeloid leukaemic cell lines and in specimens of patients with acute myeloid leukaemia (AML), using semiquantitative reverse transcription-polymerase chain reaction, and protein levels of ID1 in human myeloid leukaemic cell lines using Western blot analysis. Six of seven AML cell lines and 12 of 15 AML patient samples were found to have barely detectable ID1 mRNA. All of these cell lines showed the same levels of protein in proportion to levels of mRNA. Two of the AML cell lines with low ID1 expression, KG1 and KG-1a, were chosen for treatment with either the DNA demethylation reagent, 5-aza-2'-deoxycytidine (DAC), or the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). These treatments were alone or in combination, and ID1 expression was induced by both DAC and TSA. No hypermethylated ID1 gene promoter was detected in the majority of the cell lines and patient specimens, by methylation-specific polymerase chain reaction, suggesting that induction of ID1 in KG1 and KG-1a was not due to direct demethylation of the ID1 gene promoter. Chromatin immunoprecipitation showed that accumulation of acetyl-histone H3 and release of HDAC1 were correlated with ID1 induction by these drugs. Flow cytometric assay demonstrated more apoptosis induced by TSA or TSA in combination with DAC, in both KG-1 and KG-1a cell lines. Increase of intracellular reactive oxygen species was observed when treated with TSA.Most AML cell lines and human AML samples have very low levels of expression of ID1. TSA or TSA in combination with DAC is able to restore ID1 expression in low ID1-expressing AML cell lines by re-activating the aberrantly deacetylated promoter, and this also results in more apoptotic cell death, in which ID1 and the redox pathway may be involved.

    View details for DOI 10.1111/j.1365-2184.2007.00499.x

    View details for Web of Science ID 000252442100006

    View details for PubMedID 18211287

    View details for PubMedCentralID PMC6496488

  • Decreased expression of the histone methyltransferase SUV39H1 in AML cells reactivates hypermethylated tumor suppressor p15INK4B in the absence of promoter demethylation Scott, S., Geyer, C., DeCoteau, J. F. AMER SOC HEMATOLOGY. 2007: 106B
  • CYP2C9, CYP2C19 and CYP2D6 allele frequencies in the Ashkenazi Jewish population PHARMACOGENOMICS Scott, S., Edelmann, L., Kornreich, R., Erazo, M., Desnick, R. J. 2007; 8 (7): 721–30


    To determine and compare the cytochrome P450 (CYP)2C9, CYP2C19 and CYP2D6 allele and genotype frequencies in the Ashkenazi Jewish (AJ) population with other populations.CYP2C9, CYP2C19 and CYP2D6 genotypes were determined in 250 anonymous, unrelated, healthy AJ individuals from the greater New York (USA) metropolitan area. Genotyping was performed using the Tag-Ittrade mark Mutation Detection system and the recently redefined CYP2D6*41A allele was identified by a restriction fragment length polymorphism assay.Among the 250 AJ individuals, the CYP2C9*1, *2, *3 and *5 allele frequencies were 0.772, 0.140, 0.086 and 0.002, respectively, and the genotypes were distributed into extensive- (60.8%), intermediate- (32.8%) and poor- (6.4%) metabolizer phenotypes. The CYP2C19*1, *2 and *4 allele frequencies were 0.830, 0.152 and 0.018, respectively, and the genotypes were distributed into extensive (69.2%), intermediate (27.6%) and poor (3.2%) metabolizers. The most common CYP2D6 alleles identified were *1, *2A, *4 and *41A, and their frequencies were 0.286 0.152 0.226 and 0.140, respectively. The CYP2D6 genotypes were distributed into ultrarapid- (8.8%), extensive- (70.0%), intermediate- (16.0%) and poor- (5.2%) metabolizer phenotypes.Although the CYP2C9 allele and genotype frequencies in the AJ subjects were similar to those in other North American Caucasian populations, genotyping the CYP2C19*4 and CYP2D6*41A alleles in the AJ population resulted in the clinically relevant reclassification of the predicted metabolizer phenotypes. Inclusion of CYP2C19*4 reclassified individuals from either extensive- or intermediate- to the intermediate- or poor-metabolizer phenotypes, respectively. Inclusion of the redefined CYP2D6*41A allele increased the ultrarapid-, intermediate- and poor-metabolizer phenotype combined frequencies to 30%, indicating that approximately one in three AJ individuals may benefit from genotype-based drug selection and dosage. In addition, the ultrarapid CYP2D6 genotype frequency in the AJ population (8.8%) was approximately twofold higher than that in other North American Caucasians.

    View details for DOI 10.2217/14622416.8.7.721

    View details for Web of Science ID 000248267800006

    View details for PubMedID 18240905

  • Zebularine inhibits human acute myeloid leukemia cell growth in vitro in association with p15INK4B demethylation and reexpression EXPERIMENTAL HEMATOLOGY Scott, S. A., Lakshimikuttysamma, A., Sheridan, D. P., Sanche, S. E., Geyer, C., DeCoteau, J. F. 2007; 35 (2): 263–73


    The p15INK4B tumor suppressor is frequently silenced by promoter hypermethylation in myelodysplastic syndrome and acute myeloid leukemia (AML). Clinically approved DNA methylation inhibitors, such as 5-aza-2'-deoxycytidine, can reverse p15INK4B promoter methylation, but widespread clinical use of these inhibitors is limited by their toxicity and instability in aqueous solution. The cytidine analog zebularine is a stable DNA methylation inhibitor that has minimal toxicity in vitro and in vivo. We evaluated zebularine effects on p15INK4B reactivation and cell growth in vitro to investigate a potential role for zebularine in treating myeloid malignancies.We examined the specific effects of zebularine on reexpression of transcriptionally silenced p15INK4B and its global effects on cell cycle and apoptosis in AML cell lines and primary patient samples.Zebularine treatment of AML193, which has a densely methylated p15INK4B promoter, results in a dose-dependent increase in p15INK4B expression that correlates with CpG island promoter demethylation and enrichment of local histone acetylation. We observed enhanced p15INK4B induction following co-treatment with zebularine and the histone deacetylase inhibitor Trichostatin A. Zebularine inhibits cell proliferation, arrests cells at G(2)/M, and induces apoptosis at dosages that effectively demethylate the p15INK4B promoter. Zebularine treatment of KG-1 cells and AML patient blasts with hypermethylated p15INK4B promoters also reactivates p15INK4B reexpression and induces apoptosis.Zebularine is an effective inhibitor of p15INK4B methylation and cell growth in human AML in vitro. Our results extend the spectrum of zebularine effects to nonepithelial malignancies and provide a strong rationale for evaluating its clinical utility in the treatment of myeloid malignancies.

    View details for DOI 10.1016/j.exphem.2006.10.005

    View details for Web of Science ID 000244073100010

    View details for PubMedID 17258075

  • 5-Aza-2 '-deoxycytidine (decitabine) can relieve p21WAF1 repression in human acute myeloid leukemia by a mechanism involving release of histone deacetylase 1 (HDAC1) without requiring p21WAF1 promoter demethylation LEUKEMIA RESEARCH Scott, S. A., Dong, W. F., Ichinohasama, R., Hirsch, C., Sheridan, D., Sanche, S. E., Geyer, C. R., DeCoteau, J. F. 2006; 30 (1): 69–76


    Decitabine is a potent demethylating agent that exhibits clinical activity against myeloid malignancies. Numerous genes silenced by hypermethylation are reactivated by decitabine through a mechanism involving promoter demethylation with subsequent release of histone deacetylases (HDACs) and accumulation of acetylated histones. Recent studies indicating that decitabine also induces regional chromatin remodeling of some unmethylated genes suggest additional mechanisms of action. Decitabine reactivates unmethylated p21WAF1 in some AML cell lines but the possible occurrence of p21WAF1 methylation in AML in vivo has not been studied in detail and decitabine effects on p21WAF1 chromatin remodeling have not been reported. We found that p21WAF1 mRNA was undetectable in 6 of 24 AML patient samples and 4 of 5 AML cell lines but there was no evidence of p21WAF1 promoter methylation. However, decitabine induced p21WAF1 in AML cell lines KG-1 and KG-1a in association with release of HDAC1 and increased acetylated histone H3 at the unmethylated p21WAF1 promoter. Decitabine effects on p21WAF1 histone acetylation and induction were enhanced by the HDAC inhibitor trichostatin A and were independent of wild type p53. Our findings indicate that decitabine can relieve p21WAF1 repression in AML by a mechanism that involves release of HDAC1 without requiring promoter demethylation. Furthermore, our study provides evidence that combined decitabine and HDAC inhibitor treatment can enhance chromatin remodeling and reactivation of an unmethylated tumor suppressor gene. This latter finding is of relevance to the clinical use of these agents in AML as we found the p21WAF1 promoter to be unmethylated in vivo.

    View details for DOI 10.1016/j.leukres.2005.05.010

    View details for Web of Science ID 000233942000011

    View details for PubMedID 16043219

  • Methylation status of cyclin-dependent kinase inhibitor genes within the transforming growth factor beta pathway in human T-cell lymphoblastic lymphoma/leukemia LEUKEMIA RESEARCH Scott, S. A., Kimura, T., Dong, W. F., Ichinohasama, R., Bergen, S., Kerviche, A., Sheridan, D., DeCoteau, J. F. 2004; 28 (12): 1293–1301


    Epigenetic silencing of downstream components of the transforming growth factor beta pathway including the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B, p27KIP1 and p21CIP1 is implicated in the pathogenesis of some hematological malignancies. Loss of p15INK4B expression due to promoter methylation occurs frequently in human T-cell acute lymphoblastic leukemia (T-ALL) but the expression and methylation status of p27KIP1 remains to be characterized in T-ALL or T-cell lymphoblastic lymphoma (T-LBL). As well, while some have reported a high frequency of p21CIP1 methylation in ALL patient samples others have found the gene to be unmethylated in this disease and the relationship between p21CIP1 expression and promoter methylation has not been examined in T-LBL. Using RNase protection assays (RPA) and methylation specific PCR (MSP), we found p27KIP1 to be expressed and its promoter unmethylated in 20 of 20 (100%) and 28 of 28 (100%) T-LBL/ALL samples, respectively. In contrast, p21CIP1 mRNA was absent in 7 of 14 (50%) T-LBL biopsies and 5 of 6 (83%) T-ALL cell lines. However, like p27KIP1 there was no evidence of p21CIP1 promoter methylation by MSP or temporal temperature gradient electrophoresis (TTGE) analysis of 35 CpG sites in any of the 28 T-LBL/ALLs analyzed. Similar to T-ALL, we found p15INK4B mRNA was absent in 13 of 14 (93%) T-LBL biopsies and its promoter methylated in 6 of 10 (64%) cases. Our results indicate that p21CIP1 mRNA is absent in human T-LBL biopsies and T-ALL cell lines at a high frequency. However, unlike p15INK4B, reduced p21CIP1 expression in T-LBL/ALL is independent of dense promoter-associated CpG methylation. In contrast to some hematological malignancies p27KIP1 methylation does not appear to contribute significantly to T-LBL/ALL pathogenesis.

    View details for DOI 10.1016/j.leukres.2004.03.019

    View details for Web of Science ID 000224780200009

    View details for PubMedID 15475071

  • Microsatellite mutations of transforming growth factor-beta receptor type II and caspase-5 occur in human precursor T-cell lymphoblastic lymphomas/leukemias in vivo but are not associated with hMSH2 or hMLH1 promoter methylation LEUKEMIA RESEARCH Scott, S., Kimura, T., Ichinohasama, R., Bergen, S., Magliocco, A., Reimer, C., Kerviche, A., Sheridan, D., DeCoteau, J. F. 2003; 27 (1): 23–34


    In solid cancers, defective DNA mismatch repair (MMR) is most commonly caused by hMSH2 or hMLH1 mutations, or epigenetic silencing of hMLH1 by promoter hypermethylation, and results in the acquisition of characteristic frameshift microsatellite mutations of mononucleotide repeats located within the coding regions of defined target genes. We previously identified hMSH2 mutations in T-cell lymphoblastic lymphoma (T-LBL) patient tumor samples and others have reported coding region microsatellite mutations in T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Thus, while MMR gene mutations are known to occur in some human T-lymphoblastic tumors in vivo, it is still unknown if the coding region microsatellite mutations detected in human cell lines also occur in vivo or if hMLH1 or hMSH2 promoter hypermethylation contributes to defective MMR in these tumors. We analyzed the TGFbetaRII (A)10 and caspase-5 (A)10 coding region repeats in 16 human T-LBL/ALL patient tumor samples and identified six with microsatellite mutations in one or both repeats. There was no evidence of hMSH2 or hMLH1 promoter methylation as assessed by standard methylation specific PCR or by a novel temporal temperature gradient electrophoresis (TTGE) method that analyzed 25 and 30 CpG sites in the hMLH1 and hMSH2 promoters, respectively. Our results indicate that coding region microsatellite mutations characteristic of defective MMR occur in some human T-LBL/ALL in vivo but not as a consequence of hMLH1 or hMSH2 promoter hypermethylation. Furthermore, the identification of TGFbetaRII and caspase-5 coding region mutations in vivo implicates these genes in the pathogenesis of human T-LBL/ALL.

    View details for DOI 10.1016/S0145-2126(02)00078-4

    View details for Web of Science ID 000180568700005

    View details for PubMedID 12479849

  • MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability BLOOD Lowsky, R., Magliocco, A., Ichinohasama, R., Reitmair, A., Scott, S., Henry, M., Kadin, M. E., DeCoteau, J. F. 2000; 95 (5): 1767–72


    High-frequency microsatellite instability (MSI), defined as more than 20% unstable loci, is an inconsistent finding in hematologic malignancies; consequently, the significance of deficient DNA mismatch repair (MMR) to their pathogenesis has been questioned. To further investigate the relationship between MMR deficiency and genomic instability in hematologic malignancies, this study evaluated MSH2-/- murine lymphomas for insertion/deletion (ID) mutations within the transforming growth factor (TGF)-beta receptor type II (TbetaR-II) gene and MSI at 10 neutral microsatellites. The lymphomas displayed ID mutations within short mononucleotide runs of TbetaR-II at a high frequency, whereas nonmalignant tissue from corresponding animals lacked mutations. Loss of TbetaR-II transcripts and protein was seen in 6 of 7 murine lymphomas harboring acquired TbetaR-II mutations. In the analysis of paired nonmalignant and tumor DNA samples, low-frequency but not high-frequency MSI was found. Low-frequency MSI occurred in 8 of 20 lymphomas and 12 displayed microsatellite stability. MSI was even less frequent in nonmalignant tissue as only 3 of 20 samples displayed low-frequency MSI and 17 displayed stability. Evaluation of 20 single cell clones from the MSH2-/- lymphoma cell lines R25 and L15 identified high-frequency MSI in 4 and 2 clones, respectively. The remaining clones showed low-frequency MSI or stability. These findings suggest that acquired TbetaR-II mutations represent important inactivating events in tumor pathogenesis following MSH2 deficiency. Furthermore, for some hematolymphoid malignancies, the evaluation of cancer-associated genes for ID mutations may represent a more sensitive marker of MMR deficiency than evaluation of neutral microsatellites for high-frequency MSI. (Blood. 2000;95:1767-1772)

    View details for DOI 10.1182/blood.V95.5.1767.005k07_1767_1772

    View details for Web of Science ID 000085564700033

    View details for PubMedID 10688836