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Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa. Objectives: To perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions. Methods: We performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10−7) and EPIC arrays (p < 5.78 × 10−8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Semicontinuous data, characterized by an excess of zeros followed by a non-negative and right-skewed distribution, are frequently observed in biomedical research. Different statistical models have been proposed to investigate the association of covariates with such outcome. Motivated by the search of genetic factors associated with Neutrophil Extracellular Traps (NETs), a semicontinuous biomarker involved in thrombosis, we here investigated the impact of the selected model for semicontinuous traits in the context of a Genome Wide Association Study (GWAS). We compared three models that jointly model zero and positive values while allowing the estimation of a single association parameter of covariates with the global mean: Tobit, Negative Binomial and Compound Poisson-Gamma. We assessed the fit of these models to a sample of 657 participants of the FARIVE study measured for NETs plasma levels. For each of these three models, we performed a GWAS on NETs in FARIVE participants and results were compared. A simulation study was also conducted to evaluate the control of the type I error. Compound Poisson-Gamma and Negative Binomial models fitted NETs data observed in FARIVE better than the Tobit model. However, the Negative Binomial model suffered from an inflation of its type I error, attributable to extreme positive values of the NETs and low frequency variants. Conversely, the Compound Poisson-Gamma model was robust to both phenomena. Using the latter model, a GWAS identified a genome wide significant locus on chr21q21.3. The lead variant was rs57502213, a deletion of two nucleotides located ∼40kb upstream the non-coding RNA (miR155HG) hosting the miR-155 that was recently highlighted to have a role in NETs formation. This work indicates that the modeling strategy for a semicontinuous outcome in the framework of GWAS studies is crucial. The choice of the model should take into account the nature of the process generating zero values and the presence of extreme values. Our work also suggests that the Compound Poisson-Gamma model, while still marginally employed, can be a robust modeling strategy for GWAS analysis on a semicontinuous trait.

Background Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). Results We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P Conclusion We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.

Background: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. Methods: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n=72) and nasal brushing samples (n=97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and EGEA. Results: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P

Background: Computational biology requires the reading and comprehension of biological data files. Plain-text formats such as SAM, VCF, GTF, PDB and FASTA, often contain critical information which is obfuscated by the data structure complexity. Results: bioSyntax ( https://biosyntax.org/ ) is a freely available suite of biological syntax highlighting packages for vim, gedit, Sublime, VSCode, and less. bioSyntax improves the legibility of low-level biological data in the bioinformatics workspace. Conclusion: bioSyntax supports computational scientists in parsing and comprehending their data efficiently and thus can accelerate research output.

Background The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. Results We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. Conclusions Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1173-7) contains supplementary material, which is available to authorized users.

Efficient interventions to reduce blood triglycerides are few; newer and more tolerable intervention targets are needed. Understanding the molecular mechanisms underlying blood triglyceride levels variation is key to identifying new therapies. To explore the role of epigenetic mechanisms on triglyceride levels, a blood methylome scan was conducted in 199 individuals from 5 French-Canadian families ascertained on venous thromboembolism, and findings were replicated in 324 French unrelated patients with venous thromboembolism. Genetic context and functional relevance were investigated. Two DNA methylation sites associated with triglyceride levels were identified. The first one, located in the ABCG1 gene, was recently reported, whereas the second one, located in the promoter of the PHGDH gene, is novel. The PHGDH methylation site, cg14476101, was found to be associated with variation in triglyceride levels in a threshold manner: cg14476101 was inversely associated with triglyceride levels only when triglyceride levels were above 1.12 mmol/L (discovery P-value = 8.4 × 10−6; replication P-value = 0.0091). Public databases findings supported a functional role of cg14476101 on PHGDH expression. PHGDH catalyses the first step in the serine biosynthesis pathway. These findings highlight the role of epigenetic regulation of the PHGDH gene in triglyceride metabolism, providing novel insights on putative intervention targets.

Following publication of the original article [1], the authors reported an error in Additional file 1.

International audience; Essentials Tissue factor pathway inhibitor (TFPI) regulates the blood coagulation cascade. We replicated previously reported linkage of TFPI plasma levels to the chromosome 2q region. The putative causal locus, rs62187992, was associated with TFPI plasma levels and thrombosis. rs62187992 was marginally associated with TFPI expression in human aortic endothelial cells. Click to hear Ann Gil's presentation on new insights into thrombin activatable fibrinolysis inhibitor SUMMARY: Background Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial thromboembolism and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes. Objectives To replicate the finding of the linkage region in an independent sample, and to identify the causal locus. Methods We first performed a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study, and replicated the finding of the linkage peak on chromosome 2q (LOD = 3.06). We next defined a follow-up region that included 112 603 single nucleotide polymorphisms (SNPs) under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and the Marseille Thrombosis Association (MARTHA) Study, a study of 1033 unrelated VTE patients. SNPs with false discovery rate q-values of < 0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene Study. Results and Conclusions One SNP, rs62187992, was associated with TFPI plasma levels in all three samples (β = + 0.14 and P = 4.23 × 10(-6) combined; β = + 0.16 and P = 0.02 in the F5L Family Study; β = + 0.13 and P = 6.3 × 10(-4) in the MARTHA Study; β = + 0.17 and P = 0.03 in the AtheroGene Study), and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio 0.90, P = 0.03) in the INVENT Consortium of > 7000 cases and their controls, and was marginally associated with TFPI expression (β = + 0.19, P = 0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated.

International audience; Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.

The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P1 Mb apart. Over 90% of these pairs are replicated (FDR, There is a functional link between SNPs and epigenetic variations when they are in close range, but the long-range effect is unclear. Here, by analysing methylation quantitative trait loci, the authors demonstrate that methylation levels at CpG sites in lymphocytes are correlated with distal SNPs.

There is increasing enthusiasm regarding the use of bio-banked whole blood DNA as a model to discover methylation marks associated with biological phenotypes and generate novel mechanistic hypotheses (1–3). DNA methylation has a critical role in cell functions and is cell-type specific. Such cell specificity makes DNA methylation particularly challenging for epidemiological epigenetic investigations because disease relevant cell types might not be accessible due to practical issues such as availability, ethics, and cost associated with more complex specimen collection. Recent work suggests that agnostic methylation-wide association scan (MWAS) in peripheral blood can reflect phenotype-associated methylation marks in other tissues and cell types, with effects detected in established effector cells much stronger than effects detected in blood (4). These observations suggest that marks detected in blood are associated with functions in effector cells. The Illumina HumanMethylation450 (HM450K) array is a robust assay to measure DNA methylation across the genome (4–7). For any high-throughput technologies, and in particular for a novel assay such as the HM450K, rigorous quality control procedures are warranted and robustness of findings must be validated through independent replication to avoid reporting spurious associations. In the current issue of the Journal, Frazier-Wood et al. (8) reported the novel findings of significant negative correlations between methylation levels at two CpG sites in the CPT1A locus and plasma levels of VLDL and LDL. Methylation levels were assessed in CD4+ T-cells isolated from peripheral blood DNA using the HM450K array. Given that no independent study samples were available for replication, to circumvent this challenge, the authors adopted an internal validation method by splitting the whole sample into “discovery and replication subsamples”. This strategy provides arguments in favor of the discovered associations but does not provide evidence of robustness against spurious findings due to sampling or confounding biases or any other undetected biases present in the study sample. A robust and thorough validation strategy implies the use of independent study samples and variation in the study designs (9, 10). The validation phase is of particular importance in MWAS, as this technique is particularly subjected to confounders (3). Thus, we undertook to test for associations the two CTP1A CpG sites found associated with lipid-related traits by Frazier-Wood et al. using two independent study samples with considerable variations in their respective study design and with the design of the Frazier-Wood study. The studies had differences in sampling scheme, DNA methylation specimen, and array preprocessing approaches. The notable differences in the design and sample characteristics between the three studies are shown in Table 1. Most notable is the method for lipid measurement, nuclear magnetic resonance spectroscopy in Frazier-Wood et al. and spectrophotometry in our studies. In addition to sampling variation, and of particular interest for MWAS studies, Frazier-Wood et al. assessed DNA methylation in isolated CD4+ T-cells, while we assessed methylation in peripheral whole blood, which includes CD4+ T-cell (

Summary Background Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI. Methods 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0·05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. Findings 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value ≤0·05) between methylation at five probes across three different genes and BMI. The associations with three of these probes—cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A —were confirmed in both the primary and second replication cohorts. For every 0·1 increase in methylation β value at cg22891070, BMI was 3·6% (95% CI 2·4–4·9) higher in the discovery cohort, 2·7% (1·2–4·2) higher in the primary replication cohort, and 0·8% (0·2–1·4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1·72 × 10 −5 ) but not in skin (p=0·882). We observed a significant inverse correlation (p=0·005) between methylation at cg22891070 and expression of one HIF3A gene-expression probe in adipose tissue. Two single nucleotide polymorphisms—rs8102595 and rs3826795—had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. Interpretation Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people. Funding The European Commission, National Institute for Health Research, British Heart Foundation, and Wellcome Trust.

DNA methylation regulates gene expression by chromatin reshaping and the recruitment of various partner proteins. Dysregulation in these regulatory mechanisms can influence the individual susceptibility to some pathologies, including cardiovascular disorders. Although different cell types can have different methylation patterns, the use of DNA from blood cells has recently been proposed as an interesting tool to discover new epigenetic related pathophysiological mechanisms. This PhD project focuses on the interests of the methylome-wide association analyses as an alternative strategy to the fashion genome-wide association studies ("GWAS ") approach to identify new molecular determinants of cardiovascular risk biomarkers. For my project, I had access to two epidemiological studies collecting together 573 subjects in which DNA methylation levels from peripheral blood cells were measured by a high density DNA microarray that covers more than 300 000 CpG sites.The first work I conducted consisted in a study of blood methylome to identify methylation profiles associated with body mass index. This study led to the identification of DNA methylation marks at the HIF3A gene whose increases are associated with an increase in body mass index (Lancet, 2014. 383(9933):1990-8). These results suggest that a disruption of the metabolic pathway HIF3A gene could have an important role in the biological response to the increase of the weight. In a second work (J Lipid Res, 2014. 55(7):1189-1191), I showed that the inter-individual variability in CPT1A methylation levels in blood were associated with variability of plasma lipid levels. This work demonstrates that it is possible to detect DNA methylation marks from blood samples that could reflect epigenetic mechanisms that occur primarily in specific cells or tissues. The CPT1A gene is for example mainly expressed in the liver.During my PhD, I also studied the influence of the genetic variability on the methylation levels from blood DNA (Am J Hum Genet, 2015. 96(4):532-42, Nat Commun, 2015. 6:6326). This work has identified nearly 3000 genes whose methylation levels are associated with the presence of genetic polymorphisms, located either within these same genes (ie cis effect) or at a very large distance (more than one megabase or to another chromosome) (ie trans effect). These results open new perspectives to better understand the transcriptional regulation of various metabolic pathways., La méthylation de l'ADN permet, via des remodelages de la chromatine et le recrutement de diverses protéines partenaires, de réguler l'expression des gènes. Des défaillances dans ces mécanismes de régulation peuvent modifier la susceptibilité individuelle face à certaines pathologies, notamment cardiovasculaires. Bien que les différents types cellulaires puissent avoir différents profils de méthylation, l'utilisation de l'ADN provenant de cellules sanguines permet de découvrir de nouveaux mécanismes physiopathologiques. Ce projet de thèse porte sur l'intérêt des analyses d'association méthylome entier comme stratégie alternative aux études d'association génome entier ("GWAS " en anglais) pour identifier de nouveaux déterminants moléculaires de biomarqueurs du risque cardiovasculaire. Pour cela, j'avais à ma disposition deux études épidémiologiques rassemblant 573 sujets pour lesquels les niveaux de méthylation de l'ADN issus du sang périphérique ont été mesurés par une puce à ADN de haute densité couvrant plus de 300 000 sites CpG.Le premier travail que j'ai réalisé a consisté en une étude du méthylome sanguin pour identifier des profils de méthylation associés à l'indice de masse corporelle. Cette étude a permis d'identifier des marques de méthylation de l'ADN au sein du gène HIF3A dont les augmentations sont associées à une augmentation de l'indice de masse corporelle (Lancet, 2014. 383(9933):1990-8). Ces résultats suggèrent en outre que des perturbations de la voie métabolique du gène HIF3A pourraient avoir un rôle important dans la réponse biologique à l'augmentation du poids. Dans un second travail (J Lipid Res, 2014. 55(7):1189-1191), j'ai montré que la variabilité inter individuelle des niveaux de méthylation sanguin du gène CPT1A était associée à la variabilité des taux lipidiques plasmatiques. Ce travail démontre qu'il est possible de détecter à partir d'échantillons sanguins des marques de méthylation de l'ADN qui pourraient être le reflet de mécanismes épigénétiques plus spécifiques de certains types cellulaires ou de certains tissus. Le gène CPT1A est par exemple principalement exprimé dans le foie.Au cours de mon travail de thèse, j'ai également étudié l'influence de la variabilité génétique sur les niveaux de méthylation de l'ADN sanguin (Am J Hum Genet, 2015. 96(4):532-42, Nat Commun, 2015. 6:6326). Cette étude a permis d'identifier près de 3 milles gènes dont les niveaux de méthylation sont associés à la présence de polymorphismes génétiques, localisés soit au sein de ces mêmes gènes (c.-à-d. effet cis) soit à une très grande distance (plus d'une mégabase voire sur un autre chromosome) (c.-à-d. effet trans). Ces résultats ouvrent de nouvelles perspectives pour mieux appréhender la régulation transcriptionnelle de diverses voies métaboliques.