Nasim Bararpour

All Publications

• A comparison of deep multiomics profiles across ethnicity, geography, and age. Cell Barapour, N., Cao, J. Z., Wu, Y., Gupta, S., Hoopmann, M. R., Qin, R., Midha, M. K., Mireault, M., Juanes-Velasco, P., Hanson, C., Ahadi, S., Higgs, E., Baxter, D. H., Diener, C., Dagan-Rosenfeld, O., Hornburg, D., Che, S., Edfors, F., Church, S. J., Babu, M., Thota, D., Jin, C., Chou, T., Rego, S., Avina, M., McGuire, L., Li, J. W., Karathanos, T., Panyard, D. J., Acosta Parra, M. A., Roberts, A. K., Ranjit, A. K., Rangan, E., Almagro Armenteros, J. J., Ashland, M., Castillo, K. E., Traber, G., Ellenberger, M., Kellogg, R., Zhou, W., Rost, H., Kjellberg, M., Mishra, T., Kapil, C., Kusebauch, U., Patwardhan, S., Landeira-Viñuela, A., Hernandez, A. P., Thomsen, M. E., Mashkoor, M., Sutantiwanichkul, T., Dodig-Crnkovic, T., Bendes, A., Dahl, L., Gibbons, S. M., Rangan, P. V., Stensballe, A., Schwenk, J. M., Unwin, R. D., Fuentes, M., Sleno, L., Moritz, R. L., Mahal, L. K., Snyder, M. P. 2026; 189 (10): 3004-3024.e35

  Abstract

  Despite extensive research, molecular differences in human populations and the influence of ancestry, age, geography, and diet are poorly understood. We performed comprehensive multiomics profiling (including genomics, transcriptomics, proteomics, metabolomics, lipidomics, metallomics, glycomics, and microbiomics) on samples from 322 healthy individuals of European, East Asian, and South Asian ancestry across multiple continents. We identified ethnicity-associated molecular features linked to host metabolism, autoimmune disease risk, drug metabolism, and neurodegenerative pathways. We uncovered ancestry- and geography-related molecular changes affecting metabolism, immune function, microbiome composition, and biological aging. Specific genetic variants and gene expression differences were associated with lipid metabolism and immune regulation. Geography influenced biological age: East Asians showed lower biological age in their ancestral regions, whereas individuals of European ancestry exhibited lower biological age in the US/Canada than in Europe. Diet-microbiome metabolism interactions displayed ethnicity-specific patterns, many related to health. This open access resource advances understanding of ethnicity-environment interactions and supports precision medicine.

  View details for DOI 10.1016/j.cell.2026.04.032

  View details for PubMedID 42134306

• Metabolomic Profiles During and After a Hypertensive Disorder of Pregnancy: The EPOCH Study. International journal of molecular sciences Hlatky, M. A., Shu, C. H., Bararpour, N., Murphy, B. M., Sorondo, S. M., Leeper, N. J., Wong, F., Stevenson, D. K., Shaw, G. M., Stefanick, M. L., Boyd, H. A., Melbye, M., Sedan, O., Wong, R. J., Snyder, M. P., Aghaeepour, N., Winn, V. D. 2025; 26 (13)

  Abstract

  Hypertensive disorders of pregnancy are associated with a higher risk of later cardiovascular disease, but the mechanistic links are unknown. We recruited two groups of women, one during pregnancy and another at least two years after delivery, including both cases (with a hypertensive disorder of pregnancy) and controls (with a normotensive pregnancy). We measured metabolites using liquid chromatography-mass spectroscopy and applied machine learning to identify metabolomic signatures at three time points: antepartum, postpartum, and mid-life. The mean ages of the pregnancy cohort (58 cases, 46 controls) and the mid-life group (71 cases, 74 controls) were 33.8 and 40.8 years, respectively. The levels of 157 metabolites differed significantly between the cases and the controls antepartum, including 19 acylcarnitines, 12 gonadal steroids, 11 glycerophospholipids, nine fatty acids, six vitamin D metabolites, and four corticosteroids. The machine learning model developed using all antepartum metabolite levels discriminated well between the cases and the controls antepartum (c-index = 0.96), postpartum (c-index = 0.63), and in mid-life (c-index = 0.60). Levels of 10,20-dihydroxyeicosanoic acid best distinguished the cases from the controls both antepartum and postpartum. These data suggest that the pattern of differences in metabolites found antepartum continues to distinguish women who had a hypertensive disorder of pregnancy from women with a normotensive pregnancy for years after delivery.

  View details for DOI 10.3390/ijms26136150

  View details for PubMedID 40649926

• Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis. Nature cancer Esplin, E. D., Hanson, C., Wu, S., Horning, A. M., Barapour, N., Nevins, S. A., Jiang, L., Contrepois, K., Lee, H., Guha, T. K., Hu, Z., Laquindanum, R., Mills, M. A., Chaib, H., Chiu, R., Jian, R., Chan, J., Ellenberger, M., Becker, W. R., Bahmani, B., Khan, A., Michael, B., Weimer, A. K., Esplin, D. G., Shen, J., Lancaster, S., Monte, E., Karathanos, T. V., Ladabaum, U., Longacre, T. A., Kundaje, A., Curtis, C., Greenleaf, W. J., Ford, J. M., Snyder, M. P. 2024

  Abstract

  Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis.

  View details for DOI 10.1038/s43018-024-00831-z

  View details for PubMedID 39478120

  View details for PubMedCentralID 2706149

• Temporal dynamics of the multi-omic response to endurance exercise training. Nature 2024; 629 (8010): 174-183

  Abstract

  Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

  View details for DOI 10.1038/s41586-023-06877-w

  View details for PubMedID 38693412

  View details for PubMedCentralID PMC11062907

• The mitochondrial multi-omic response to exercise training across rat tissues. Cell metabolism Amar, D., Gay, N. R., Jimenez-Morales, D., Jean Beltran, P. M., Ramaker, M. E., Raja, A. N., Zhao, B., Sun, Y., Marwaha, S., Gaul, D. A., Hershman, S. G., Ferrasse, A., Xia, A., Lanza, I., Fernández, F. M., Montgomery, S. B., Hevener, A. L., Ashley, E. A., Walsh, M. J., Sparks, L. M., Burant, C. F., Rector, R. S., Thyfault, J., Wheeler, M. T., Goodpaster, B. H., Coen, P. M., Schenk, S., Bodine, S. C., Lindholm, M. E. 2024

  Abstract

  Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

  View details for DOI 10.1016/j.cmet.2023.12.021

  View details for PubMedID 38701776

• People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites: a case-control study. Frontiers in cardiovascular medicine Frias, M. A., Pagano, S., Bararpour, N., Sidibé, J., Kamau, F., Fétaud-Lapierre, V., Hudson, P., Thomas, A., Lecour, S., Strijdom, H., Vuilleumier, N. 2024; 11: 1343361

  Abstract

  This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease.This case-control study conducted in South Africa consisted of control volunteers (n = 50), people living with HIV (PLWH) on ART (n = 50), and untreated PLWH (n = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed.Anti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS).Cardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated.HIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation.

  View details for DOI 10.3389/fcvm.2024.1343361

  View details for PubMedID 38414919

  View details for PubMedCentralID PMC10896987

• SMYD3: a new regulator of adipocyte precursor proliferation at the early steps of differentiation. International journal of obesity (2005) Sajic, T., Ferreira Gomes, C. K., Gasser, M., Caputo, T., Bararpour, N., Landaluce-Iturriria, E., Augsburger, M., Walter, N., Hainard, A., Lopez-Mejia, I. C., Fracasso, T., Thomas, A., Gilardi, F. 2023

  Abstract

  In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to a hypertrophic growth that is accompanied by the development of inflammation and metabolic dysfunction. However, the molecular mechanisms underlying the fine-tuned regulation of adipose tissue expansion are far from being understood.We analyzed by mass spectrometry-based proteomics visceral white adipose tissue (vWAT) samples collected from C57BL6 mice fed with a HFD for 8 weeks. A subset of these mice, called low inflammation (Low-INFL), showed reduced adipose tissue inflammation, as opposed to those developing the expected inflammatory response (Hi-INFL). We identified the discriminants between Low-INFL and Hi-INFL vWAT samples and explored their function in Adipose-Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes.vWAT proteomics allowed us to quantify 6051 proteins. Among the candidates that most differentiate Low-INFL from Hi-INFL vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in Low-INFL, as compared to Hi-INFL. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was so far unknown, was another top-scored hit. SMYD3 expression was significantly higher in Low-INFL vWAT, as confirmed by western blot analysis. Using AD-hMSCs in culture, we found that SMYD3 mRNA and protein levels decrease rapidly during the adipocyte differentiation. Moreover, SMYD3 knock-down before adipocyte differentiation resulted in reduced H3K4me3 and decreased cell proliferation, thus limiting the number of cells available for adipogenesis.Our study describes an important role of SMYD3 as a newly discovered regulator of adipocyte precursor proliferation during the early steps of adipogenesis.

  View details for DOI 10.1038/s41366-023-01450-x

  View details for PubMedID 38148333

  View details for PubMedCentralID 4859313

• Arsenic induces metabolome remodeling in mature human adipocytes. Toxicology Gasser, M., Lenglet, S., Bararpour, N., Sajic, T., Vaucher, J., Wiskott, K., Augsburger, M., Fracasso, T., Gilardi, F., Thomas, A. 2023: 153672

  Abstract

  Human lifetime exposure to arsenic through drinking water, food supply or industrial pollution leads to its accumulation in many organs such as liver, kidneys, lungs or pancreas but also adipose tissue. Recently, population-based studies revealed the association between arsenic exposure and the development of metabolic diseases such as obesity and type 2 diabetes. To shed light on the molecular bases of such association, we determined the concentration that inhibited 17% of cell viability and investigated the effects of arsenic acute exposure on adipose-derived human mesenchymal stem cells differentiated in vitro into mature adipocytes and treated with sodium arsenite (NaAsO2, 10nM to 10µM). Untargeted metabolomics and gene expression analyses revealed a strong dose-dependent inhibition of lipogenesis and lipolysis induction, reducing the cellular ability to store lipids. These dysregulations were emphasized by the inhibition of the cellular response to insulin, as shown by the perturbation of several genes and metabolites involved in the mentioned biological pathways. Our study highlighted the activation of an adaptive oxidative stress response with the strong induction of metallothioneins and increased glutathione levels in response to arsenic accumulation that could exacerbate the decreased insulin sensitivity of the adipocytes. Arsenic exposure strongly affected the expression of arsenic transporters, responsible for arsenic influx and efflux, and induced a pro-inflammatory state in adipocytes by enhancing the expression of the inflammatory interleukin 6 (IL6). Collectively, our data showed that an acute exposure to low levels of arsenic concentrations alters key adipocyte functions, highlighting its contribution to the development of insulin resistance and the pathogenesis of metabolic disorders.

  View details for DOI 10.1016/j.tox.2023.153672

  View details for PubMedID 37956786

• Dynamic lipidome alterations associated with human health, disease and ageing. Nature metabolism Hornburg, D., Wu, S., Moqri, M., Zhou, X., Contrepois, K., Bararpour, N., Traber, G. M., Su, B., Metwally, A. A., Avina, M., Zhou, W., Ubellacker, J. M., Mishra, T., Schüssler-Fiorenza Rose, S. M., Kavathas, P. B., Williams, K. J., Snyder, M. P. 2023

  Abstract

  Lipids can be of endogenous or exogenous origin and affect diverse biological functions, including cell membrane maintenance, energy management and cellular signalling. Here, we report >800 lipid species, many of which are associated with health-to-disease transitions in diabetes, ageing and inflammation, as well as cytokine-lipidome networks. We performed comprehensive longitudinal lipidomic profiling and analysed >1,500 plasma samples from 112 participants followed for up to 9 years (average 3.2 years) to define the distinct physiological roles of complex lipid subclasses, including large and small triacylglycerols, ester- and ether-linked phosphatidylethanolamines, lysophosphatidylcholines, lysophosphatidylethanolamines, cholesterol esters and ceramides. Our findings reveal dynamic changes in the plasma lipidome during respiratory viral infection, insulin resistance and ageing, suggesting that lipids may have roles in immune homoeostasis and inflammation regulation. Individuals with insulin resistance exhibit disturbed immune homoeostasis, altered associations between lipids and clinical markers, and accelerated changes in specific lipid subclasses during ageing. Our dataset based on longitudinal deep lipidome profiling offers insights into personalized ageing, metabolic health and inflammation, potentially guiding future monitoring and intervention strategies.

  View details for DOI 10.1038/s42255-023-00880-1

  View details for PubMedID 37697054

  View details for PubMedCentralID 7736650

• The polyclonal path to malignant transformation in familial adenomatous polyposis Schenck, R. O., Khan, A., Horning, A., Esplin, E. D., Monte, E., Wu, S., Hanson, C., Bararpour, N., Neves, S., Jiang, L., Contrepois, K., Lee, H., Guha, T. K., Hu, Z., Laquindanum, R., Mills, M. A., Chaib, H., Chiu, R., Jian, R., Chan, J., Ellenberger, M., Becker, W. R., Bahmani, B., Michael, B., Shen, J., Lancaster, S., Ladabaum, U., Kundaje, A., Longacre, T. A., Greenleaf, W. J., Ford, J. M., Snyder, M. P., Curtis, C. AMER ASSOC CANCER RESEARCH. 2023

  View details for DOI 10.1158/1538-7445.AM2023-3497

  View details for Web of Science ID 001008499100430

• Multi-omics microsampling for the profiling of lifestyle-associated changes in health. Nature biomedical engineering Shen, X., Kellogg, R., Panyard, D. J., Bararpour, N., Castillo, K. E., Lee-McMullen, B., Delfarah, A., Ubellacker, J., Ahadi, S., Rosenberg-Hasson, Y., Ganz, A., Contrepois, K., Michael, B., Simms, I., Wang, C., Hornburg, D., Snyder, M. P. 2023

  Abstract

  Current healthcare practices are reactive and use limited physiological and clinical information, often collected months or years apart. Moreover, the discovery and profiling of blood biomarkers in clinical and research settings are constrained by geographical barriers, the cost and inconvenience of in-clinic venepuncture, low sampling frequency and the low depth of molecular measurements. Here we describe a strategy for the frequent capture and analysis of thousands of metabolites, lipids, cytokines and proteins in 10 μl of blood alongside physiological information from wearable sensors. We show the advantages of such frequent and dense multi-omics microsampling in two applications: the assessment of the reactions to a complex mixture of dietary interventions, to discover individualized inflammatory and metabolic responses; and deep individualized profiling, to reveal large-scale molecular fluctuations as well as thousands of molecular relationships associated with intra-day physiological variations (in heart rate, for example) and with the levels of clinical biomarkers (specifically, glucose and cortisol) and of physical activity. Combining wearables and multi-omics microsampling for frequent and scalable omics may facilitate dynamic health profiling and biomarker discovery.

  View details for DOI 10.1038/s41551-022-00999-8

  View details for PubMedID 36658343

• Toxicity and Metabolomic Impact of Cobalt, Chromium, and Nickel Exposure on HepaRG Hepatocytes. Chemical research in toxicology Bellouard, M., Gasser, M., Lenglet, S., Gilardi, F., Bararpour, N., Augsburger, M., Thomas, A., Alvarez, J. 2022

  Abstract

  Cobalt, chromium, and nickel are used in orthopedic prostheses. They can be released, accumulate in many organs, and be toxic. The aim of this study is to evaluate the cytotoxicity of these metals on human hepatocytes and to improve our knowledge of their cellular toxicity mechanisms by metabolomic analysis. HepaRG cells were incubated for 48 h with increasing concentrations of metals to determine their IC50. Then, a nontargeted metabolomic study using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was done at IC50 and at a lower concentration (100 nM), near to those found in the blood and liver of patients with prostheses. IC50 were defined at 940, 2, and 1380 muM for Co, Cr, and Ni, respectively. In vitro, Cr appears to be much more toxic than Co and Ni. Metabolomic analysis revealed the disruption of metabolic pathways from the low concentration of 100 nM, in particular tryptophan metabolism and lipid metabolism illustrated by an increase in phenylacetylglycine, a marker of phospholipidosis, for all three metals. They also appear to be responsible for oxidative stress. Dysregulation of these pathways impacts hepatocyte metabolism and may result in hepatotoxicity. Further investigations on accessible biological matrices should be conducted to correlate our in vitro results with the clinical data of prostheses-bearing patients.

  View details for DOI 10.1021/acs.chemrestox.1c00429

  View details for PubMedID 35442019

• Cadmium acute exposure induces metabolic and transcriptomic perturbations in human mature adipocytes. Toxicology Gasser, M., Lenglet, S., Bararpour, N., Sajic, T., Wiskott, K., Augsburger, M., Fracasso, T., Gilardi, F., Thomas, A. 2022: 153153

  Abstract

  Obesity is considered as a major public health concern with strong economic and social burdens. Exposure to pollutants such as heavy metals can contribute to the development of obesity and its associated metabolic disorders, including type 2 diabetes and cardiovascular diseases. Adipose tissue is an endocrine and paracrine organ that plays a key role in the development of these diseases and is one of the main target of heavy metal accumulation. In this study, we determined by inductively coupled plasma mass spectrometry cadmium concentrations in human subcutaneous and visceral adipose tissues, ranging between 2.5nM and 2.5M. We found a positive correlation between cadmium levels and age, sex and smoking status and a negative correlation between Cd and body mass index. Based on cadmium adipose tissue concentrations found in humans, we investigated the effects of cadmium exposure, at concentrations between 1nM and 10M, on adipose-derived human mesenchymal stem cells differentiated into mature adipocytes in vitro. Transcriptomic analysis highlighted that such exposure altered the expression of genes involved in trace element homeostasis and heavy metal detoxification, such as Solute Carrier Family transporters and metallothioneins. This effect correlated with zinc level alteration in cells and cellular media. Interestingly, dysregulation of zinc homeostasis and transporters has been particularly associated with the development of obesity and type 2 diabetes. Moreover, we found that cadmium exposure induces the pro-inflammatory state of the adipocytes by enhancing the expression of genes such as IL-6, IL-1B and CCL2, cytokines also induced in obesity. Finally, cadmium modulates various adipocyte functions such as the insulin response signaling pathway and lipid homeostasis. Collectively, our data identified some of the cellular mechanisms by which cadmium alters adipocyte functions, thus highlighting new facets of its potential contribution to the progression of metabolic disorders.

  View details for DOI 10.1016/j.tox.2022.153153

  View details for PubMedID 35301059

• Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity. British journal of pharmacology Magliocco, G., Desmeules, J., Matthey, A., Quirós-Guerrero, L. M., Bararpour, N., Joye, T., Marcourt, L., Queiroz, E. F., Wolfender, J. L., Gloor, Y., Thomas, A., Daali, Y. 2021; 178 (23): 4708-4725

  Abstract

  Individualized assessment of cytochrome P450 2D6 (CYP2D6) activity is usually performed through phenotyping following administration of a probe drug to measure the enzyme's activity. To avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-burdensome tools for real-time phenotyping of CYP2D6 could significantly contribute to precision medicine. This study focuses on the identification of markers of the CYP2D6 enzyme in human biofluids using an LC-high-resolution mass spectrometry-based metabolomic approach.Plasma and urine samples from healthy volunteers were analysed before and after intake of a daily dose of paroxetine 20 mg over 7 days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants.We report four metabolites of solanidine and two unknown compounds as possible novel CYP2D6 markers. Mean relative intensities of these features were significantly reduced during the inhibition session compared with the control session (n = 37). Semi-quantitative analysis showed that the largest decrease (-85%) was observed for the ion m/z 432.3108 normalized to solanidine (m/z 398.3417). Mean relative intensities of these ions were significantly higher in the CYP2D6 normal-ultrarapid metabolizer group (n = 37) compared with the poor metabolizer group (n = 6). Solanidine intensity was more than 15 times higher in CYP2D6-deficient individuals compared with other volunteers.The applied untargeted metabolomic strategy identified potential novel markers capable of semi-quantitatively predicting CYP2D6 activity, a promising discovery for personalized medicine.

  View details for DOI 10.1111/bph.15651

  View details for PubMedID 34363609

  View details for PubMedCentralID PMC9290485

• Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes. Scientific reports Porcu, E., Gilardi, F., Darrous, L., Yengo, L., Bararpour, N., Gasser, M., Marques-Vidal, P., Froguel, P., Waeber, G., Thomas, A., Kutalik, Z. 2021; 11 (1): 6197

  Abstract

  The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.

  View details for DOI 10.1038/s41598-021-85684-7

  View details for PubMedID 33737653

  View details for PubMedCentralID PMC7973501

• DBnorm as an R package for the comparison and selection of appropriate statistical methods for batch effect correction in metabolomic studies. Scientific reports Bararpour, N., Gilardi, F., Carmeli, C., Sidibe, J., Ivanisevic, J., Caputo, T., Augsburger, M., Grabherr, S., Desvergne, B., Guex, N., Bochud, M., Thomas, A. 2021; 11 (1): 5657

  Abstract

  As a powerful phenotyping technology, metabolomics provides new opportunities in biomarker discovery through metabolome-wide association studies (MWAS) and the identification of metabolites having a regulatory effect in various biological processes. While mass spectrometry-based (MS) metabolomics assays are endowed with high throughput and sensitivity, MWAS are doomed to long-term data acquisition generating an overtime-analytical signal drift that can hinder the uncovering of real biologically relevant changes. We developed "dbnorm", a package in the R environment, which allows for an easy comparison of the model performance of advanced statistical tools commonly used in metabolomics to remove batch effects from large metabolomics datasets. "dbnorm" integrates advanced statistical tools to inspect the dataset structure not only at the macroscopic (sample batches) scale, but also at the microscopic (metabolic features) level. To compare the model performance on data correction, "dbnorm" assigns a score that help users identify the best fitting model for each dataset. In this study, we applied "dbnorm" to two large-scale metabolomics datasets as a proof of concept. We demonstrate that "dbnorm" allows for the accurate selection of the most appropriate statistical tool to efficiently remove the overtime signal drift and to focus on the relevant biological components of complex datasets.

  View details for DOI 10.1038/s41598-021-84824-3

  View details for PubMedID 33707505

  View details for PubMedCentralID PMC7952378

• Detecting early myocardial ischemia in rat heart by MALDI imaging mass spectrometry. Scientific reports Aljakna Khan, A., Bararpour, N., Gorka, M., Joye, T., Morel, S., Montessuit, C. A., Grabherr, S., Fracasso, T., Augsburger, M., Kwak, B. R., Thomas, A., Sabatasso, S. 2021; 11 (1): 5135

  Abstract

  Diagnostics of myocardial infarction in human post-mortem hearts can be achieved only if ischemia persisted for at least 6-12 h when certain morphological changes appear in myocardium. The initial 4 h of ischemia is difficult to diagnose due to lack of a standardized method. Developing a panel of molecular tissue markers is a promising approach and can be accelerated by characterization of molecular changes. This study is the first untargeted metabolomic profiling of ischemic myocardium during the initial 4 h directly from tissue section. Ischemic hearts from an ex-vivo Langendorff model were analysed using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) at 15 min, 30 min, 1 h, 2 h, and 4 h. Region-specific molecular changes were identified even in absence of evident histological lesions and were segregated by unsupervised cluster analysis. Significantly differentially expressed features were detected by multivariate analysis starting at 15 min while their number increased with prolonged ischemia. The biggest significant increase at 15 min was observed for m/z 682.1294 (likely corresponding to S-NADHX-a damage product of nicotinamide adenine dinucleotide (NADH)). Based on the previously reported role of NAD+/NADH ratio in regulating localization of the sodium channel (Nav1.5) at the plasma membrane, Nav1.5 was evaluated by immunofluorescence. As expected, a fainter signal was observed at the plasma membrane in the predicted ischemic region starting 30 min of ischemia and the change became the most pronounced by 4 h. Metabolomic changes occur early during ischemia, can assist in identifying markers for post-mortem diagnostics and improve understanding of molecular mechanisms.

  View details for DOI 10.1038/s41598-021-84523-z

  View details for PubMedID 33664384

  View details for PubMedCentralID PMC7933419

• In situ metabolomic changes in rat hippocampus after acute cocaine administration INTERNATIONAL JOURNAL OF MASS SPECTROMETRY Joye, T., Bararpour, N., Augsburger, M., Boutrel, B., Thomas, A. 2019; 437: 87-91

  View details for DOI 10.1016/j.ijms.2017.12.001

  View details for Web of Science ID 000456800900012

• Separation of blood microsamples by exploiting sedimentation at the microscale. Scientific reports Forchelet, D., Béguin, S., Sajic, T., Bararpour, N., Pataky, Z., Frias, M., Grabherr, S., Augsburger, M., Liu, Y., Charnley, M., Déglon, J., Aebersold, R., Thomas, A., Renaud, P. 2018; 8 (1): 14101

  Abstract

  Microsample analysis is highly beneficial in blood-based testing where cutting-edge bioanalytical technologies enable the analysis of volumes down to a few tens of microliters. Despite the availability of analytical methods, the difficulty in obtaining high-quality and standardized microsamples at the point of collection remains a major limitation of the process. Here, we detail and model a blood separation principle which exploits discrete viscosity differences caused by blood particle sedimentation in a laminar flow. Based on this phenomenon, we developed a portable capillary-driven microfluidic device that separates blood microsamples collected from finger-pricks and delivers 2 µL of metered serum for bench-top analysis. Flow cytometric analysis demonstrated the high purity of generated microsamples. Proteomic and metabolomic analyses of the microsamples of 283 proteins and 1351 metabolite features was consistent with samples generated via a conventional centrifugation method. These results were confirmed by a clinical study scrutinising 8 blood markers in obese patients.

  View details for DOI 10.1038/s41598-018-32314-4

  View details for PubMedID 30237536

  View details for PubMedCentralID PMC6147834

• Proteome and Metabolome of Subretinal Fluid in Central Serous Chorioretinopathy and Rhegmatogenous Retinal Detachment: A Pilot Case Study. Translational vision science & technology Kowalczuk, L., Matet, A., Dor, M., Bararpour, N., Daruich, A., Dirani, A., Behar-Cohen, F., Thomas, A., Turck, N. 2018; 7 (1): 3

  Abstract

  To investigate the molecular composition of subretinal fluid (SRF) in central serous chorioretinopathy (CSCR) and rhegmatogenous retinal detachment (RRD) using proteomics and metabolomics.SRF was obtained from one patient with severe nonresolving bullous CSCR requiring surgical subretinal fibrin removal, and two patients with long-standing RRD. Proteins were trypsin-digested, labeled with Tandem-Mass-Tag and fractionated according to their isoelectric point for identification and quantification by tandem mass spectrometry. Independently, metabolites were extracted on cold methanol/ethanol, and identified by untargeted ultra-high performance liquid chromatography and high-resolution mass spectrometry. Bioinformatics analyses were conducted.In total, 291 proteins and 651 metabolites were identified in SRF samples. Compared with RRD, 128 proteins (77 downregulated; 51 upregulated) and 76 metabolites (43 downregulated; 33 upregulated) differed in the SRF from CSCR. Protein and metabolites notably deregulated in CSCR were related to glycolysis/gluconeogenesis, inflammation (including serum amyloid P component, versican), alternative complement pathway (complement factor H and complement factor H-related protein), cellular adhesion, biliary acid metabolism (farnesoid X receptor/retinoid X receptor), and gluco- and mineralocorticoid systems (aldosterone, angiotensin, and corticosteroid-binding globulin).Proteomics and metabolomics can be performed on SRF. A unique SRF sample from CSCR exhibited a distinct molecular profile compared with RRD.This first comparative multiomics analysis of SRF improved the understanding of CSCR and RRD pathophysiology. It identified pathways potentially involved in the better photoreceptor preservation in CSCR, suggesting neuroprotective targets that will require additional confirmation.

  View details for DOI 10.1167/tvst.7.1.3

  View details for PubMedID 29359109

  View details for PubMedCentralID PMC5772832