Themistocles Assimes, Postdoctoral Faculty Sponsor
The Propagation of Racial Disparities in Cardiovascular Genomics Research.
Circulation. Genomic and precision medicine
Genomics research has improved our understanding of the genetic basis for human traits and diseases. This progress is now being translated into clinical care as we move toward a future of precision medicine. Many hope that expanded use of genomic testing will improve disease screening, diagnosis, risk stratification, and treatment. In many respects, cardiovascular medicine is leading this charge. However, most cardiovascular genomics research has been conducted in populations of primarily European ancestry. This bias has critical downstream effects. Here, we review the current disparities in cardiovascular genomics research, and we outline how these disparities propagate forward through all phases of the translational pipeline. If not adequately addressed, biases in genomics research will further compound the existing health disparities that face underrepresented and marginalized populations.
View details for DOI 10.1161/CIRCGEN.121.003178
View details for PubMedID 34461749
Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.
2021; 11 (1): 11645
Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n=6062). Significant associations were tested for replication in the Penn Medicine Biobank (n=5737) and the Million Veteran Program (n=82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR]=6.4, 95% confidence interval [CI] 2.6-15.6, p=4.2*10-5), which was replicated in the Penn Medicine Biobank (OR=1.6, 95% CI 1.2-2.4, p=6.0*10-3) and Million Veteran Program (OR=1.5, 95% CI 1.2-1.8, p=1.8*10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR=2.8, 95% CI 1.7-4.5, p=2.6*10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.
View details for DOI 10.1038/s41598-021-91113-6
View details for PubMedID 34079032
Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals with Atrial Fibrillation.
Circulation. Genomic and precision medicine
Background - Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA2DS2-VASc) don't include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS). Methods - Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank, both independently and integrated with clinical risk factors. The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Results - Compared with the currently recommended risk tool (CHA2DS2-VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Using this improved tool, >115,000 people with AF would have improved risk classification in the US. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.06 to 1.23)). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson's correlation coefficient: -0.018). Conclusions - In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.
View details for DOI 10.1161/CIRCGEN.120.003168
View details for PubMedID 34029116
- Inherited Extremes of Aortic Diameter Confer Risk for a Specific Class of Congenital Heart Disease. Circulation. Genomic and precision medicine 2020
A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population.
2020; 16 (11): e1008802
The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.
View details for DOI 10.1371/journal.pgen.1008802
View details for PubMedID 33226994
Role of GSTM1 and GSTT1 genotypes in differentiated thyroid cancer and interaction with lifestyle factors: Results from case-control studies in France and New Caledonia.
2020; 15 (1): e0228187
GSTM1 and GSTT1 are involved in detoxification of xenobiotics, products of oxidative stress and in steroid hormones metabolism. We investigated whether GSTM1 and GSTT1 gene deletion was associated with DTC risk and explored interaction with non-genetic risk factors of DTC.The study included 661 DTC cases and 736 controls from two case-control studies conducted in France and New Caledonia. Odds ratios (OR) and their confidence interval (CI) for DTC associated with GST genotypes, alcohol drinking, tobacco smoking, body mass index and hormonal factors were calculated using logistic regression models.Results are presented for Europeans and Melanesians combined, as no heterogeneity between groups was detected. We found that DTC risk increased with obesity and decrease with alcohol drinking. After stratification by gene deletion status, the OR for obesity was 5.75, (95%CI 2.25-14.7) among individuals with GSTT1 and GSTM1-deleted genotype, and 1.26, (95%CI 0.89-1.77) in carriers of both genes (p-interaction = 0.02). The OR for drinking ≥1 glass/week was 0.33 (95%CI 0.15-0.74) in GSTT1-null individuals while it was 1.01 (95%CI 0.67-1.52) in non-null carriers of the gene (p-interaction = 0.01). No interaction between GST genotypes and other non-genetic risk factors was detected.GSTM1 and GSTT1 genotypes may modulate the DTC risk associated with BMI and alcohol consumption.
View details for DOI 10.1371/journal.pone.0228187
View details for PubMedID 31999731
View details for PubMedCentralID PMC6992216
- Performance of Polygenic Risk Scores for Coronary Artery Disease in the Million Veteran Program LIPPINCOTT WILLIAMS & WILKINS. 2019
Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 9q22.33 and 14q13.3 detects novel candidate functional SNPs in Europeans from metropolitan France and Melanesians from New Caledonia
INTERNATIONAL JOURNAL OF CANCER
2016; 139 (3): 617–27
Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.
View details for DOI 10.1002/ijc.30088
View details for Web of Science ID 000378418100015
View details for PubMedID 26991144
Associations of Genetically Predicted Lipoprotein (a) Levels with Cardiovascular Traits in Individuals of European and African Ancestry.
Circulation. Genomic and precision medicine
Background - Lipoprotein (a) [Lp(a)] levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with 1) atherosclerotic cardiovascular disease (ASCVD) subtypes: coronary heart disease (CHD), cerebrovascular disease (CVD), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA); and 2) non-ASCVD phenotypes, stratified by ancestry. Methods - We performed 1) Mendelian randomization (MR) analyses for previously reported cardiovascular associations, and 2) phenome-wide MR (MR-PheWAS) analyses for novel associations. Analyses were stratified by ancestry in electronic MEdical Records and GEnomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804,507 EA and 103,580 AA participants. Results - In MR analyses using the combined cohort, a 1-standard deviation (SD) genetic increase in Lp(a) level was associated with ASCVD subtypes in EA - odds ratio and 95% confidence interval for CHD 1.28(1.16-1.41); CVD 1.14(1.07-1.21); PAD 1.22(1.11-1.34); AAA 1.28(1.17-1.40); in AA the effect estimate was lower than in EA and nonsignificant for CHD 1.11(0.99-1.24) and CVD 1.06(0.99-1.14) but similar for PAD 1.16(1.01-1.33) and AAA 1.34(1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34(1.10-1.62), mitral valve disorders 1.18(1.09-1.27), congestive heart failure 1.12(1.05-1.19), and chronic kidney disease 1.07(1.01-1.14). In AA no significant associations were noted for aortic valve disorders 1.08(0.94-1.25), mitral valve disorders 1.02(0.89-1.16), congestive heart failure 1.02(0.95-1.10), or chronic kidney disease 1.05(0.99-1.12). MR-PheWAS identified novel associations in EA with arterial thromboembolic disease, non-aortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. Conclusions - Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with ASCVD in four major arterial beds in EA but only with PAD and AAA in AA. Additional, novel cardiovascular associations were detected in EA.
View details for DOI 10.1161/CIRCGEN.120.003354
View details for PubMedID 34282949
BROAD CLINICAL MANIFESTATIONS OF POLYGENIC RISK FOR CORONARY ARTERY DISEASE IN THE WOMEN'S HEALTH INITIATIVE
ELSEVIER SCIENCE INC. 2021: 1511
View details for Web of Science ID 000647487501519
The V122I Variant in Hereditary Transthyretin-Mediated Amyloidosis is Significantly Associated with Polyneuropathy
CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2020: S96
View details for Web of Science ID 000579889600256
Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction.
2020; 11 (1): 4432
Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases=270/Ncontrols=5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication=2.19*10-12, OR=1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P<5*10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P=0.021, OR=1.82[95%CI:1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P=1.28*10-17, HR=0.91[95%CI:0.89-0.93], for MI) and Million Veteran Program (P=9.33*10-36, OR=0.95[95%CI:0.94-0.96], for CAD; P=3.35*10-6, OR=0.96[95%CI:0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.
View details for DOI 10.1038/s41467-020-17558-x
View details for PubMedID 32887874
Horizontal and Vertical Pleiotropy Linking Coronary Artery Disease, Traumatic Experiences, and Post-traumatic Stress in > 650,000 Individuals
ELSEVIER SCIENCE INC. 2020: S52–S53
View details for Web of Science ID 000535308200125
- Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program. Circulation 2020
Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.
We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
View details for DOI 10.1038/s41588-020-0637-y
View details for PubMedID 32541925
Cardiac Imaging of Aortic Valve Area from 34,287 UK Biobank Participants Reveal Novel Genetic Associations and Shared Genetic Comorbidity with Multiple Disease Phenotypes.
Circulation. Genomic and precision medicine
Background - The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases. Methods - From a sample of 34,287 white British-ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac MRI sequences of the aortic valve. Aortic valve area measurements were submitted to genome-wide association testing, followed by polygenic risk scoring and phenome-wide screening to identify genetic comorbidities. Results - A genome-wide association study of aortic valve area in these UK Biobank participants showed three significant associations, indexed by rs71190365 (chr13:50764607, DLEU1, p=1.8×10-9), rs35991305 (chr12:94191968, CRADD, p=3.4×10-8) and chr17:45013271:C:T (GOSR2, p=5.6×10-8). Replication on an independent set of 8,145 unrelated European-ancestry participants showed consistent effect sizes in all three loci, although rs35991305 did not meet nominal significance. We constructed a polygenic risk score for aortic valve area, which in a separate cohort of 311,728 individuals without imaging demonstrated that smaller aortic valve area is predictive of increased risk for aortic valve disease (Odds Ratio 1.14, p=2.3×10-6). After excluding subjects with a medical diagnosis of aortic valve stenosis (remaining n=308,683 individuals), phenome-wide association of >10,000 traits showed multiple links between the polygenic score for aortic valve disease and key health-related comorbidities involving the cardiovascular system and autoimmune disease. Genetic correlation analysis supports a shared genetic etiology with between aortic valve area and birthweight along with other cardiovascular conditions. Conclusions - These results illustrate the use of automated phenotyping of cardiac imaging data from the general population to investigate the genetic etiology of aortic valve disease, perform clinical prediction, and uncover new clinical and genetic correlates of cardiac anatomy.
View details for DOI 10.1161/CIRCGEN.120.003014
View details for PubMedID 33125279
- Highlights From the American Heart Association's EPI|LIFESTYLE 2019 Scientific Sessions. Journal of the American Heart Association 2019; 8 (11): e012925
- Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease CIRCULATION 2019; 139 (16): 1889–99
- CONGENITAL HEART DISEASE CONFERS SUBSTANTIAL RISK OF ACQUIRED CARDIOVASCULAR DISEASE AMONGST BRITISH ADULTS ELSEVIER SCIENCE INC. 2018: 553
Hormonal and reproductive risk factors of papillary thyroid cancer: A population-based case-control study in France.
2017; 48: 78–84
The three times higher incidence of thyroid cancer in women compared to men points to a role of female sex hormones in its etiology. However the effects of these factors are poorly understood. We analyzed the association between thyroid cancer and hormonal and reproductive factors among women enrolled in CATHY, a population-based case-control study conducted in France. The study included 430 cases of papillary thyroid cancer and 505 controls frequency-matched on age and area of residence. The odds ratios for thyroid cancer increased with age at menarche (p trend 0.05). Postmenopausal women were at increased risk, as compared to premenopausal women, particularly if menopause followed an ovariectomy, and for women with age at menopause <55years. In addition, use of oral contraceptives and menopausal hormone therapy reduced the association with thyroid cancer by about one third, and breastfeeding by 27%. Overall, these findings provide evidence that the risk of thyroid cancer increases with later age at menarche and after menopause, and decreases with use of oral contraceptives and menopausal hormone therapy. These findings confirm an implication of hormonal factors in papillary thyroid cancer risk, whose mechanisms need to be elucidated.
View details for DOI 10.1016/j.canep.2017.04.001
View details for PubMedID 28426980