Germain M.,French Institute of Health and Medical Research |
Germain M.,University Pierre and Marie Curie |
Germain M.,Institute for Cardiometabolism and Nutrition ICAN |
Chasman D.I.,Harvard University |
And 72 more authors.
American Journal of Human Genetics | Year: 2015
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. © 2015 The American Society of Human Genetics.
Eyries M.,University Pierre and Marie Curie |
Eyries M.,Institute for Cardiometabolism and Nutrition ICAN |
Montani D.,University Paris - Sud |
Montani D.,University of Turin |
And 30 more authors.
Nature Genetics | Year: 2014
Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation. PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension. PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission. Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension. © 2014 Nature America, Inc.
Machado R.D.,University of Lincoln |
Southgate L.,Queen Mary, University of London |
Southgate L.,King's College London |
Eichstaedt C.A.,University of Heidelberg |
And 25 more authors.
Human Mutation | Year: 2015
Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools. © 2015 Wiley Periodicals, Inc.
Brnne I.,University of Lübeck |
Brnne I.,German Research Center for Cardiovascular Research |
Civelek M.,University of California at Los Angeles |
Vilne B.,TU Munich |
And 26 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015
Objective-Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes. Approach and Results-All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters. The latter included expression quantitative trait loci, tissue specificity, and miRNA binding. High priority candidate genes were further identified based on literature searches and our experimental data. We conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, we obtained evidence that genetic variants at CAD loci affect 98 genes which had not been linked to CAD previously. Conclusions-Our results substantially revise the list of likely candidates for CAD and suggest that genome-wide association studies efforts in other diseases may benefit from similar bioinformatics analyses. © 2015 American Heart Association, Inc.
Suchon P.,Aix - Marseille University |
Suchon P.,Laboratory of Hematology |
Al Frouh F.,Aix - Marseille University |
Henneuse A.,Aix - Marseille University |
And 14 more authors.
Thrombosis and Haemostasis | Year: 2016
Identifying women at risk of venous thromboembolism (VTE) is a major public health issue. The objective of this study was to identify environmental and genetic determinants of VTE risk in a large sample of women under combined oral contraceptives (COC). A total of 968 women who had had one event of VTE during COC use were compared to 874 women under COC but with no personal history of VTE. Clinical data were collected and a systematic thrombophilia screening was performed together with ABO blood group assessment. After adjusting for age, family history, and type and duration of COC use, main environmental determinants of VTE were smoking (odds ratio [OR] =1.65, 95 % confidence interval [1.30-2.10]) and a body mass index higher than 35 kg.m-2 (OR=3.46 [1.81-7.03]). In addition, severe inherited thrombophilia (OR=2.13 [1.32-3.51]) and non-O blood groups (OR=1.98 [1.57-2.49]) were strong genetic risk factors for VTE. Family history poorly predicted thrombophilia as its prevalence was similar in patients with or without first degree family history of VTE (29.3 % vs 23.9 %, p=0.09). In conclusion, this study confirms the influence of smoking and obesity and shows for the first time the impact of ABO blood group on the risk of VTE in women under COC. It also confirms the inaccuracy of the family history of VTE to detect inherited thrombophilia. © Schattauer 2016.
Ojeda F.M.,University of Hamburg |
Muller C.,University of Hamburg |
Muller C.,German Center for Cardiovascular Research |
Bornigen D.,University of Hamburg |
And 10 more authors.
Genomics, Proteomics and Bioinformatics | Year: 2016
Prognostic models based on survival data frequently make use of the Cox proportional hazards model. Developing reliable Cox models with few events relative to the number of predictors can be challenging, even in low-dimensional datasets, with a much larger number of observations than variables. In such a setting we examined the performance of methods used to estimate a Cox model, including (i) full model using all available predictors and estimated by standard techniques, (ii) backward elimination (BE), (iii) ridge regression, (iv) least absolute shrinkage and selection operator (lasso), and (v) elastic net. Based on a prospective cohort of patients with manifest coronary artery disease (CAD), we performed a simulation study to compare the predictive accuracy, calibration, and discrimination of these approaches. Candidate predictors for incident cardiovascular events we used included clinical variables, biomarkers, and a selection of genetic variants associated with CAD. The penalized methods, i.e., ridge, lasso, and elastic net, showed a comparable performance, in terms of predictive accuracy, calibration, and discrimination, and outperformed BE and the full model. Excessive shrinkage was observed in some cases for the penalized methods, mostly on the simulation scenarios having the lowest ratio of a number of events to the number of variables. We conclude that in similar settings, these three penalized methods can be used interchangeably. The full model and backward elimination are not recommended in rare event scenarios. © 2016 The Authors.
Marchand A.,Institute for Cardiometabolism and Nutrition ICAN |
Atassi F.,Institute for Cardiometabolism and Nutrition ICAN |
Atassi F.,French Institute of Health and Medical Research |
Atassi F.,University Pierre and Marie Curie |
And 22 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016
We identified murine miR-322, orthologous to human miR-424, as a new regulator of insulin receptor, IGF-receptor and sirtuin 4 mRNA in vitro and in vivo in the heart and found that miR-322/424 is highly expressed in the heart of mice. C57Bl/6N mice fed 10 weeks of high fat diet (HFD) presented signs of cardiomyopathy and a stable miR-322 cardiac level while cardiac function was slightly affected in 11 week-old ob/ob which overexpressed miR-322. We thus hypothesized that mmu-miR-322 could be protective against cardiac consequences of hyperinsulinemia and hyperlipidemia. We overexpressed or knocked-down mmu-miR-322 using AAV9 and monitored cardiac function in wild-type C57Bl/6N mice fed a control diet (CD) or a HFD and in ob/ob mice. The fractional shortening progressively declined while the left ventricle systolic diameter increased in HFD mice infected with an AAVcontrol or with an AAVsponge (decreasing miR-322 bioavailability) but also in ob/ob mice infected with AAVsponge. Similar observations were also found in CD-fed mice infected with AAVsponge. On the contrary over-expressing miR-322 with AAVmiR-322 was efficient in protecting the heart from HFD effects in C57Bl/6N mice. This cardioprotection could be associated with the regulation of identified targets IGF1R, INSR and CD1, a decrease in insulin signaling pathway and an enrichment of genes involved in mitochondrial function and fatty acid oxidation as demonstrated by transcriptome analysis. Altogether, these results emphasize miR-322 as a new potential therapeutic target against cardiac consequences of metabolic syndrome, which represents an increasing burden in the western countries. © 2016.
Morange P.-E.,La Timone Hospital |
Morange P.-E.,French Institute of Health and Medical Research |
Morange P.-E.,Aix - Marseille University |
Suchon P.,La Timone Hospital |
And 5 more authors.
Thrombosis and Haemostasis | Year: 2015
Venous thrombosis (VT) is a common multifactorial disease with a genetic component that was first suspected nearly 60 years ago. In this review, we document the genetic determinants of the disease, and update recent findings delivered by the application of highthroughput genotyping and sequencing technologies. To date, 17 genes have been robustly demonstrated to harbour genetic variations associated with VT risk: ABO, F2, F5, F9, F11, FGG, GP6, KNG1, PROC, PROCR, PROS1, SERPINC1, SLC44A2, STXBP5, THBD, TSPAN15 and VWF. The common polymorphisms are estimated to account only for a modest part (~5 %) of the VT heritability. Much remains to be done to fully disentangle the exact genetic (and epigenetic) architecture of the disease. A large suite of powerful tools and research strategies can be deployed on the large collections of patients that have already been assembled (and additional are ongoing). © Schattauer 2015.
PubMed | University Paris Diderot, Service dHepatogastroenterologie, Institute for Cardiometabolism and Nutrition ICAN, University of Modena and Reggio Emilia and University Pierre and Marie Curie
Type: Journal Article | Journal: BMJ open gastroenterology | Year: 2016
Type-2 diabetes mellitus (T2DM) is a risk factor for progressive non-alcoholic fatty liver disease (NAFLD). Drugs commonly prescribed in patients with T2DM may affect liver histology by interfering with lipid metabolism and insulin resistance/secretion.We studied if statins or antidiabetic agents were associated with non-alcoholic steatohepatitis (NASH) and significant fibrosis (SF).We performed a cross-sectional study of 346 diabetics with biopsy-proven NAFLD. T2DM was defined as fasting glucose 7mmol/L or glycated haemoglobin 6.5% and/or use of antidiabetics. NASH was defined according to the FLIP algorithm and SF as F2-4 Kleiners stages.84% of patients were on antidiabetic therapy and 45% on statins. NASH and SF were present in 57% and 48% of patients. Statin-treated patients were older, more frequently male and with poorer glycaemic control despite more frequent antidiabetic therapy than those without statins; however, the prevalence of NASH (57%vs56%, p=0.868) and SF (48%vs48%, p=0.943) was not different between statin users and non-users. NASH was more common in patients on metformin or insulin than in those not treated with these drugs (60%vs47%, p=0.026; 68%vs53%, p=0.017). SF was more common in those treated with sulfonylureas (57%vs44%, p=0.030). Multivariate analyses confirmed that use of statins was independently and negatively associated with both NASH (OR (95% CI) 0.57 (0.32 to 1.01), p=0.055) and SF (OR (95% CI) 0.47 (0.26 to 0.84), p=0.011). Moreover, we found independent associations between insulin use and NASH (OR (95% CI) 2.24 (1.11 to 4.54), p=0.025) and sulfonylureas use and SF (OR (95% CI) 2.04 (1.11 to 3.74), p=0.022).Several medications used in patients with diabetes are differently associated with NAFLD histology. Statin use is negatively associated, while insulin and sulfonylureas are positively associated with NASH and SF. A wider use of statins may be warranted in this high-risk population.
Aschard H.,Harvard University |
Vilhjalmsson B.J.,Harvard University |
Vilhjalmsson B.J.,Cambridge Broad Institute |
Greliche N.,Paris-Sorbonne University |
And 7 more authors.
American Journal of Human Genetics | Year: 2014
Many human traits are highly correlated. This correlation can be leveraged to improve the power of genetic association tests to identify markers associated with one or more of the traits. Principal component analysis (PCA) is a useful tool that has been widely used for the multivariate analysis of correlated variables. PCA is usually applied as a dimension reduction method: the few top principal components (PCs) explaining most of total trait variance are tested for association with a predictor of interest, and the remaining components are not analyzed. In this study we review the theoretical basis of PCA and describe the behavior of PCA when testing for association between a SNP and correlated traits. We then use simulation to compare the power of various PCA-based strategies when analyzing up to 100 correlated traits. We show that contrary to widespread practice, testing only the top PCs often has low power, whereas combining signal across all PCs can have greater power. This power gain is primarily due to increased power to detect genetic variants with opposite effects on positively correlated traits and variants that are exclusively associated with a single trait. Relative to other methods, the combined-PC approach has close to optimal power in all scenarios considered while offering more flexibility and more robustness to potential confounders. Finally, we apply the proposed PCA strategy to the genome-wide association study of five correlated coagulation traits where we identify two candidate SNPs that were not found by the standard approach. © 2014 The American Society of Human Genetics.