241 results on '"François Cambien"'
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2. Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy
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Matthias Heinig, Michiel E. Adriaens, Sebastian Schafer, Hanneke W. M. van Deutekom, Elisabeth M. Lodder, James S. Ware, Valentin Schneider, Leanne E. Felkin, Esther E. Creemers, Benjamin Meder, Hugo A. Katus, Frank Rühle, Monika Stoll, François Cambien, Eric Villard, Philippe Charron, Andras Varro, Nanette H. Bishopric, Alfred L. George, Cristobal dos Remedios, Aida Moreno-Moral, Francesco Pesce, Anja Bauerfeind, Franz Rüschendorf, Carola Rintisch, Enrico Petretto, Paul J. Barton, Stuart A. Cook, Yigal M. Pinto, Connie R. Bezzina, and Norbert Hubner
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Genetics ,Gene expression ,eQTL ,Dilated cardiomyopathy ,Heart ,Biology (General) ,QH301-705.5 ,QH426-470 - Abstract
Abstract Background Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. Results Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. Conclusions RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.
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- 2017
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3. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.
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Ulrike Esslinger, Sophie Garnier, Agathe Korniat, Carole Proust, Georgios Kararigas, Martina Müller-Nurasyid, Jean-Philippe Empana, Michael P Morley, Claire Perret, Klaus Stark, Alexander G Bick, Sanjay K Prasad, Jennifer Kriebel, Jin Li, Laurence Tiret, Konstantin Strauch, Declan P O'Regan, Kenneth B Marguiles, Jonathan G Seidman, Pierre Boutouyrie, Patrick Lacolley, Xavier Jouven, Christian Hengstenberg, Michel Komajda, Hakon Hakonarson, Richard Isnard, Eloisa Arbustini, Harald Grallert, Stuart A Cook, Christine E Seidman, Vera Regitz-Zagrosek, Thomas P Cappola, Philippe Charron, François Cambien, and Eric Villard
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Medicine ,Science - Abstract
AimsDilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.Methods and results116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-valueConclusionWe identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
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- 2017
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4. Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis
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Stefan Blankenberg, Dominique Stengel, Hans J. Rupprecht, Christoph Bickel, Ju¨rgen Meyer, François Cambien, Laurence Tiret, and Ewa Ninio
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inflammation ,atherosclerosis ,platelet-activating factor ,Biochemistry ,QD415-436 - Abstract
Inflammation underlies both onset and perpetuation of atherosclerosis. Plasma lipoproteins transport the platelet-activating factor-acetylhydrolase (PAF-AH) with potentially anti-inflammatory activities. Our aim was to determine whether PAF-AH activity was associated with inflammatory markers and with coronary artery disease (CAD). PAF-AH activity and a panel of inflammatory mediators were measured in plasma of 496 patients with CAD and in 477 controls; 276 patients presented with stable angina pectoris and 220 with acute coronary syndrome (ACS). Individuals within the highest quartile of PAF-AH activity had an 1.8-fold increase in CAD risk [95% confidence interval (CI), 1.01 to 3.2; P = 0.048] compared with those in the first quartile (adjusted for clinical and metabolic factors). When excluding individuals receiving statin and angiotensin-converting enzyme-inhibitor medication, individuals within the highest quartile of PAF-AH activity revealed a 3.9-fold increase in CAD risk (95% CI, 2.0 to 7.7; P < 0.0001). In these subjects, the plasma PAF-AH activity increased gradually in stable angina and in ACS both in men (P < 0.0001) and in women (P < 0.001), as compared with controls.No correlation was found between PAF-AH levels and those of common markers of inflammation. This study and the previous ones raise the important issue of whether PAF-AH is simply a marker of risk or directly promotes atherosclerosis.
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- 2003
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5. Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes.
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Jonas Carlsson Almlöf, Per Lundmark, Anders Lundmark, Bing Ge, Tomi Pastinen, Cardiogenics Consortium, Alison H Goodall, François Cambien, Panos Deloukas, Willem H Ouwehand, and Ann-Christine Syvänen
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Medicine ,Science - Abstract
We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10(-7) to 9.5×10(-89). The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.
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- 2014
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6. Identification of two polymorphisms in the promoter of the microsomal triglyceride transfer protein (MTP) gene: lack of association with lipoprotein profiles
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Stefan-Martin Herrmann, Odette Poirier, Viviane Nicaud, Alun Evans, Jean-Bernard Ruidavets, Gerard Luc, Dominique Arveiler, Chen Bao-Sheng, and François Cambien
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microsomal triglyceride transfer protein ,polymorphism ,lipid variables ,atherosclerosis ,myocardial infarction ,Biochemistry ,QD415-436 - Abstract
The microsomal triglyceride transfer protein (MTP) catalyzes the transfer of triglyceride, cholesteryl ester, and phosphatidylcholine between phospholipid surfaces. The 97-kD subunit imparts lipid transfer activity and thus plays a role in the assembly of apolipoprotein B (apoB)-containing lipoproteins. We tested whether polymorphisms in the promoter region of the large subunit of the MTP gene might be related to different plasma lipid variables, atherosclerosis, and the risk of myocardial infarction (MI). We screened 838 bp in the promoter region of the MTP gene by PCR-SSCP and identified two polymorphisms at positions −400 (MTP/−400 (A→t)) and −164 (MTP/−164 (T→c)), the latter being situated on a putative sterol responsive element (SRE) consensus sequence. The two polymorphisms, investigated in 622 male patients with MI and in 728 age-matched controls participating in the ECTIM Study, were in nearly complete linkage disequilibrium (|D′| = ′0.98, less frequent alleles being preferentially associated, P < 0.001). There were no significant differences in genotype or allele frequencies between patients with MI and controls. Moreover, no significant associations between the two promoter polymorphisms and several lipid variables measured in the control groups of the ECTIM Study or coronary artery stenosis, angiographically assessed in patients with MI, were detected. We conclude that these MTP polymorphisms are unrelated to lipid variables or coronary heart disease in this study.—Herrmann, S-M., O. Poirier, V. Nicaud, A. Evans, J-B. Ruidavets, G. Luc, D. Arveiler, C. Bao-Sheng, and F. Cambien. Identification of two polymorphisms in the promoter of the microsomal triglyceride transfer protein (MTP) gene: lack of association with lipoprotein profiles. J. Lipid Res. 1998. 39: 2432–2435.
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- 1998
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7. Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.
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Sophie Garnier, Vinh Truong, Jessy Brocheton, Tanja Zeller, Maxime Rovital, Philipp S Wild, Andreas Ziegler, Cardiogenics Consortium, Thomas Munzel, Laurence Tiret, Stefan Blankenberg, Panos Deloukas, Jeannette Erdmann, Christian Hengstenberg, Nilesh J Samani, Heribert Schunkert, Willem H Ouwehand, Alison H Goodall, François Cambien, and David-Alexandre Trégouët
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Genetics ,QH426-470 - Abstract
In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9) haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4)-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies) that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4) (~0.05/412), 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.
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- 2013
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8. GUESS-ing polygenic associations with multiple phenotypes using a GPU-based evolutionary stochastic search algorithm.
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Leonardo Bottolo, Marc Chadeau-Hyam, David I Hastie, Tanja Zeller, Benoit Liquet, Paul Newcombe, Loic Yengo, Philipp S Wild, Arne Schillert, Andreas Ziegler, Sune F Nielsen, Adam S Butterworth, Weang Kee Ho, Raphaële Castagné, Thomas Munzel, David Tregouet, Mario Falchi, François Cambien, Børge G Nordestgaard, Fredéric Fumeron, Anne Tybjærg-Hansen, Philippe Froguel, John Danesh, Enrico Petretto, Stefan Blankenberg, Laurence Tiret, and Sylvia Richardson
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Genetics ,QH426-470 - Abstract
Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n = 3,175), when compared with the largest published meta-GWAS (n > 100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space.
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- 2013
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9. Graphical modeling of gene expression in monocytes suggests molecular mechanisms explaining increased atherosclerosis in smokers.
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Ricardo A Verdugo, Tanja Zeller, Maxime Rotival, Philipp S Wild, Thomas Münzel, Karl J Lackner, Henri Weidmann, Ewa Ninio, David-Alexandre Trégouët, François Cambien, Stefan Blankenberg, and Laurence Tiret
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Medicine ,Science - Abstract
Smoking is a risk factor for atherosclerosis with reported widespread effects on gene expression in circulating blood cells. We hypothesized that a molecular signature mediating the relation between smoking and atherosclerosis may be found in the transcriptome of circulating monocytes. Genome-wide expression profiles and counts of atherosclerotic plaques in carotid arteries were collected in 248 smokers and 688 non-smokers from the general population. Patterns of co-expressed genes were identified by Independent Component Analysis (ICA) and network structure of the pattern-specific gene modules was inferred by the PC-algorithm. A likelihood-based causality test was implemented to select patterns that fit models containing a path "smoking→gene expression→plaques". Robustness of the causal inference was assessed by bootstrapping. At a FDR ≤0.10, 3,368 genes were associated to smoking or plaques, of which 93% were associated to smoking only. SASH1 showed the strongest association to smoking and PPARG the strongest association to plaques. Twenty-nine gene patterns were identified by ICA. Modules containing SASH1 and PPARG did not show evidence for the "smoking→gene expression→plaques" causality model. Conversely, three modules had good support for causal effects and exhibited a network topology consistent with gene expression mediating the relation between smoking and plaques. The network with the strongest support for causal effects was connected to plaques through SLC39A8, a gene with known association to HDL-cholesterol and cellular uptake of cadmium from tobacco, while smoking was directly connected to GAS6, a gene reported to have anti-inflammatory effects in atherosclerosis and to be up-regulated in the placenta of women smoking during pregnancy. Our analysis of the transcriptome of monocytes recovered genes relevant for association to smoking and atherosclerosis, and connected genes that before, were only studied in separate contexts. Inspection of correlation structure revealed candidates that would be missed by expression-phenotype association analysis alone.
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- 2013
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10. Correction: Comprehensive Exploration of the Effects of miRNA SNPs on Monocyte Gene Expression.
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Nicolas Greliche, Tanja Zeller, Philipp S. Wild, Maxime Rotival, Arne Schillert, Andreas Ziegler, Panos Deloukas, Jeanette Erdmann, Christian Hengstenberg, Willem H. Ouwehand, Nilesh J. Samani, Heribert Schunkert, Thomas Munzel, Karl J. Lackner, François Cambien, Alison H. Goodall, Laurence Tiret, Stefan Blankenberg, and David-Alexandre Trégouët
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Medicine ,Science - Published
- 2012
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11. Powerful identification of cis-regulatory SNPs in human primary monocytes using allele-specific gene expression.
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Jonas Carlsson Almlöf, Per Lundmark, Anders Lundmark, Bing Ge, Seraya Maouche, Harald H H Göring, Ulrika Liljedahl, Camilla Enström, Jessy Brocheton, Carole Proust, Tiphaine Godefroy, Jennifer G Sambrook, Jennifer Jolley, Abigail Crisp-Hihn, Nicola Foad, Heather Lloyd-Jones, Jonathan Stephens, Rhian Gwilliam, Catherine M Rice, Christian Hengstenberg, Nilesh J Samani, Jeanette Erdmann, Heribert Schunkert, Tomi Pastinen, Panos Deloukas, Alison H Goodall, Willem H Ouwehand, François Cambien, and Ann-Christine Syvänen
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Medicine ,Science - Abstract
A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.
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- 2012
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12. Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression.
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Nicolas Greliche, Tanja Zeller, Philipp S Wild, Maxime Rotival, Arne Schillert, Andreas Ziegler, Cardiogenics Consortium, Panos Deloukas, Jeanette Erdmann, Christian Hengstenberg, Willem H Ouwehand, Nilesh J Samani, Heribert Schunkert, Thomas Munzel, Karl J Lackner, François Cambien, Alison H Goodall, Laurence Tiret, Stefan Blankenberg, and David-Alexandre Trégouët
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Medicine ,Science - Abstract
We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3'UTR regions (3utrSNPs). We then conducted a genome-wide search for marginal miSNPs effects and pairwise miSNPs × 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expression of LYZ and in trans the expression of CNTN6, CTRC, COPZ2, KRT9, LRRFIP1, NOD1, PCDHA6, ST5 and TRAF3IP2 genes, supporting the role of hsa-mir-1279 as a regulator of several genes in monocytes. In addition, we identified two robust miSNPs × 3utrSNPs interactions, one involving HLA-DPB1 rs1042448 and hsa-mir-219-1 rs107822, the second the H1F0 rs1894644 and hsa-mir-659 rs5750504, modulating the expression of the associated genes.As some of the aforementioned genes have previously been reported to reside at disease-associated loci, our findings provide novel arguments supporting the hypothesis that the genetic variability of miRNAs could also contribute to the susceptibility to human diseases.
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- 2012
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13. Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.
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Maxime Rotival, Tanja Zeller, Philipp S Wild, Seraya Maouche, Silke Szymczak, Arne Schillert, Raphaele Castagné, Arne Deiseroth, Carole Proust, Jessy Brocheton, Tiphaine Godefroy, Claire Perret, Marine Germain, Medea Eleftheriadis, Christoph R Sinning, Renate B Schnabel, Edith Lubos, Karl J Lackner, Heidi Rossmann, Thomas Münzel, Augusto Rendon, Cardiogenics Consortium, Jeanette Erdmann, Panos Deloukas, Christian Hengstenberg, Patrick Diemert, Gilles Montalescot, Willem H Ouwehand, Nilesh J Samani, Heribert Schunkert, David-Alexandre Tregouet, Andreas Ziegler, Alison H Goodall, François Cambien, Laurence Tiret, and Stefan Blankenberg
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Genetics ,QH426-470 - Abstract
One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.
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- 2011
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14. The choice of the filtering method in microarrays affects the inference regarding dosage compensation of the active X-chromosome.
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Raphaële Castagné, Maxime Rotival, Tanja Zeller, Philipp S Wild, Vinh Truong, David-Alexandre Trégouët, Thomas Munzel, Andreas Ziegler, François Cambien, Stefan Blankenberg, and Laurence Tiret
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Medicine ,Science - Abstract
BackgroundThe hypothesis of dosage compensation of genes of the X chromosome, supported by previous microarray studies, was recently challenged by RNA-sequencing data. It was suggested that microarray studies were biased toward an over-estimation of X-linked expression levels as a consequence of the filtering of genes below the detection threshold of microarrays.Methodology/principal findingsTo investigate this hypothesis, we used microarray expression data from circulating monocytes in 1,467 individuals. In total, 25,349 and 1,156 probes were unambiguously assigned to autosomes and the X chromosome, respectively. Globally, there was a clear shift of X-linked expressions toward lower levels than autosomes. We compared the ratio of expression levels of X-linked to autosomal transcripts (X∶AA) using two different filtering methods: 1. gene expressions were filtered out using a detection threshold irrespective of gene chromosomal location (the standard method in microarrays); 2. equal proportions of genes were filtered out separately on the X and on autosomes. For a wide range of filtering proportions, the X∶AA ratio estimated with the first method was not significantly different from 1, the value expected if dosage compensation was achieved, whereas it was significantly lower than 1 with the second method, leading to the rejection of the hypothesis of dosage compensation. We further showed in simulated data that the choice of the most appropriate method was dependent on biological assumptions regarding the proportion of actively expressed genes on the X chromosome comparative to the autosomes and the extent of dosage compensation.Conclusion/significanceThis study shows that the method used for filtering out lowly expressed genes in microarrays may have a major impact according to the hypothesis investigated. The hypothesis of dosage compensation of X-linked genes cannot be firmly accepted or rejected using microarray-based data.
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- 2011
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15. Genetics of venous thrombosis: insights from a new genome wide association study.
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Marine Germain, Noémie Saut, Nicolas Greliche, Christian Dina, Jean-Charles Lambert, Claire Perret, William Cohen, Tiphaine Oudot-Mellakh, Guillemette Antoni, Marie-Christine Alessi, Diana Zelenika, François Cambien, Laurence Tiret, Marion Bertrand, Anne-Marie Dupuy, Luc Letenneur, Mark Lathrop, Joseph Emmerich, Philippe Amouyel, David-Alexandre Trégouët, and Pierre-Emmanuel Morange
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Medicine ,Science - Abstract
BACKGROUND: Venous Thrombosis (VT) is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a genome-wide association study (GWAS) based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10(-8) and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance. CONCLUSIONS/SIGNIFICANCE: This study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.
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- 2011
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16. Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.
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Klaus Stark, Ulrike B Esslinger, Wibke Reinhard, George Petrov, Thomas Winkler, Michel Komajda, Richard Isnard, Philippe Charron, Eric Villard, François Cambien, Laurence Tiret, Marie-Claude Aumont, Olivier Dubourg, Jean-Noël Trochu, Laurent Fauchier, Pascal Degroote, Anette Richter, Bernhard Maisch, Thomas Wichter, Christa Zollbrecht, Martina Grassl, Heribert Schunkert, Patrick Linsel-Nitschke, Jeanette Erdmann, Jens Baumert, Thomas Illig, Norman Klopp, H-Erich Wichmann, Christa Meisinger, Wolfgang Koenig, Peter Lichtner, Thomas Meitinger, Arne Schillert, Inke R König, Roland Hetzer, Iris M Heid, Vera Regitz-Zagrosek, and Christian Hengstenberg
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Genetics ,QH426-470 - Abstract
Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10⁻⁶, OR = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻⁴, OR = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.
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- 2010
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17. Genetics and beyond--the transcriptome of human monocytes and disease susceptibility.
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Tanja Zeller, Philipp Wild, Silke Szymczak, Maxime Rotival, Arne Schillert, Raphaele Castagne, Seraya Maouche, Marine Germain, Karl Lackner, Heidi Rossmann, Medea Eleftheriadis, Christoph R Sinning, Renate B Schnabel, Edith Lubos, Detlev Mennerich, Werner Rust, Claire Perret, Carole Proust, Viviane Nicaud, Joseph Loscalzo, Norbert Hübner, David Tregouet, Thomas Münzel, Andreas Ziegler, Laurence Tiret, Stefan Blankenberg, and François Cambien
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Medicine ,Science - Abstract
BACKGROUND: Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS: To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P
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- 2010
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18. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
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Magdalena Harakalova, Benjamin Meder, Philippe Charron, Manuel Gómez-Bueno, Jorg J. A. Calis, François Cambien, David-Alexandre Trégouët, Maurizia Grasso, Steven McGinn, Uwe Völker, Thomas Meitinger, Stefan Weiss, L. Duboscq-Bidot, Richard Dorent, Vera Regitz-Zagrosek, Folkert W. Asselbergs, Hélène Blanché, Olivier Dubourg, Patrick Lacolley, Pierre Boutouyrie, Delphine Bacq-Daian, Vincent Fontaine, Volker Ruppert, Marine Germain, K Lehnert, Jean-Noël Trochu, Stuart A. Cook, Angélique Curjol, Brendan J. Keating, Ibticem Raji, Anne Boland, J. Erdmann, Michael Morley, Jean-François Aupetit, Paloma Remior, Luigi Tavazzi, Gérard Roizès, Michal Mokry, Konstantin Strauch, Richard Isnard, Jean-Philippe Empana, Robert Olaso, Kenneth B. Marguiles, Zofia T. Bilińska, Stephan B. Felix, Marcus Dörr, Thomas P. Cappola, Stefan Blankenberg, Jan Haas, Céline Besse, Jean-François Deleuze, Christine E. Seidman, Christian Hengstenberg, Jessica van Setten, Hakon Hakonarson, Sanjay K Prasad, Daiane Hemerich, Pascal de Groote, Thomas Wichter, Alain van Mil, Michel Komajda, Renee Maas, Carole Proust, Declan P. O'Regan, Xavier Jouven, Ganapathi Varma Saripella, Georgios Kararigas, Eloisa Arbustini, Jin Li, Klaus Stark, Laurent Fauchier, Flavie Ader, Melanie Waldenberger, Martina Müller-Nurasyid, Eric Villard, Sophie Garnier, Cardiology, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique-Hôpitaux de Paris, Fondation Leducq, Société Française de Cardiologie, Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München, Université de Bordeaux, Medical Research Council, ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University Medical Center [Utrecht], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Pennsylvania, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), National Heart Centre Singapore (NHCS), Children’s Hospital of Philadelphia (CHOP ), University of Regensburg, Royal Brompton Hospital, Imperial College London, Istituti Clinici Scientifici Maugeri [Pavia] (IRCCS Pavia - ICS Maugeri), Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University Medical Center of the Johannes Gutenberg-University Mainz, Perelman School of Medicine, Harvard Medical School [Boston] (HMS), University of Iceland [Reykjavik], Heidelberg University, Stanford University Medical School, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universität zu Lübeck = University of Lübeck [Lübeck], Universitätklinikum Gießen und Marburg GmbH, Maria Cecilia Hospital [Cotignola], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital cardiologique, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier Saint Joseph - Saint Luc [Lyon], National Institute of Cardiology [Varsovie, Pologne], University of Medicine Greifswald, Centre de Référence Maladies Cardiaques Héréditaires, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Swedish University of Agricultural Sciences (SLU), Centre d'Etude du Polymorphisme Humain (CEPH), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité), Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Groupe Hospitalier Paris Saint Joseph, Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), and University College of London [London] (UCL)
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Cardiac & Cardiovascular Systems ,Cardiomyopathy, Dilated/genetics ,[SDV]Life Sciences [q-bio] ,Signal Transducing/genetics ,Dilated cardiomyopathy ,Genome-wide association study ,Adaptor Proteins, Signal Transducing/genetics ,030204 cardiovascular system & hematology ,TAURINE ,0302 clinical medicine ,GWAS ,Medicine ,POSITION STATEMENT ,1102 Cardiorespiratory Medicine and Haematology ,Genetics ,0303 health sciences ,education.field_of_study ,Genetic Predisposition to Disease/genetics ,Adaptor Proteins ,4C-sequencing ,Polymorphism, Single Nucleotide/genetics ,Genetic risk score ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,Single Nucleotide/genetics ,Cardiomyopathy, Dilated ,Cardiomyopathy ,Population ,Locus (genetics) ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Chromosomes ,03 medical and health sciences ,Systolic/genetics ,Heart Failure, Systolic/genetics ,SNP ,Animals ,Humans ,Genetic Predisposition to Disease ,Allele ,Polymorphism ,education ,Imputation ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,Heart Failure ,Science & Technology ,business.industry ,WORKING GROUP ,1103 Clinical Sciences ,medicine.disease ,Genetic architecture ,Cardiovascular System & Hematology ,Dilated/genetics ,Cardiovascular System & Cardiology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,business ,Apoptosis Regulatory Proteins ,Heart Failure, Systolic ,Genome-Wide Association Study - Abstract
Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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- 2021
19. Genome wide association analysis in dilated cardiomyopathy revealed two new susceptibility loci for systolic heart failure
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Magdalena Harakalova, François Cambien, David A. Tregouet, Folkert W. Asselbergs, Michal Mokry, P. Charron, Stefan Weiss, Sophie Garnier, J. van Setten, Eric Villard, Jean-François Deleuze, Carole Proust, L. Duboscq-Bidot, Anne Boland, and Marcus Dörr
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Genetics ,business.industry ,Genomics ,Dilated cardiomyopathy ,Genome-wide association study ,medicine.disease ,Heart failure ,medicine ,Genome-Wide Association Analysis ,Allele ,Cardiology and Cardiovascular Medicine ,business ,Functional genomics ,Gene - Abstract
We conducted the largest Genome Wide Association Study performed so far in Dilated Cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death. Using a discovery phase of 2,719 cases and 4,440 controls and a replication phase of 584 independent cases and 966 controls, we identified and replicated two new DCM-associated loci, one on chromosome 3p (meta-analysis OR = 1.36 [1.25 - 1.48], p=5.3 10–13) and the second on chromosome 22q (meta-analysis OR = 1.33 [1.22 - 1.46], p=5.0 10–10), while confirming the two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. We estimated the global heritability to 31% ± 8%. The genetic risk score constructed from the number of lead risk-alleles at these 4 loci revealed a 27% risk increased in individuals with 8 risk-alleles compared to the 5 risk alleles reference group (OR = 1.27 [1.14–1.42]). The two association signals were then fine-mapped by combining in silico and functional genomics investigations (as 4C-sequencing on iPSC-derived cardiomyocytes). While a few genes remain candidates at the second locus and deserve further investigations, our work clearly identified one gene as responsible for the association at the first locus whose role in the pathophysiology of DCM is supported by recent observations in human and mice. As the biological pathway in which this gene is involved is a potential target for pharmacological agents, our finding opens novel therapeutic perspectives for treating or preventing heart failure. We are convinced that these results provide new findings that add both on the understanding of the genetic architecture of heart failure and on potential new players involved in the pathophysiology of this devastating disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): GENMED Laboratory of Excellence on Medical Genomics, DETECTIN-HF project (ERA-CVD framework), Assistance Publique-Hôpitaux de Paris, Délégation à la recherche clinique, the “Fondation LEDUCQ”, the PROMEX charitable foundation, the Société Française de Cardiologie/Fédération Française de Cardiologie, the Deutsche Forschungsgemeinschaft, The Federal Ministry of Education and Research and the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania, The German Center for Cardiovascular Research (DZHK), Hospitals NIHR Biomedical Research Centre, NWO VENI grant (no. 016.176.136)
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- 2020
20. Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosome 3p25.1 and 22q11.23
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Céline Besse, François Cambien, Folkert W. Asselbergs, Robert Olaso, Jeanette Erdman, Benjamin Meder, Stephan B. Felix, Stefan Weiss, Laurent Fauchier, Konstantin Strauch, Luigi Tavazzi, Anne Boland, Gérard Roizès, Pascal DeGroote, Renee Maas, Melanie Waldenberger, Ganapathi Varma Saripella, Pablo García-Pavía, Brendan J. Keating, Vera Regitz-Zagrosek, Marine Germain, Stefan Blankenberg, Jessica van Setten, Eloisa Arbustini, Pierre Boutouyrie, Carole Proust, Delphine Bacq-Daian, Hemerich Daiane, Sophie Garnier, Michal Mokry, Richard Dorent, Martina Müller-Nurasyid, Philippe Charron, Maurizia Grasso, Steven Mc Ginn, Vincent Fontaine, Uwe Völker, Patrick Lacolley, Thomas Meitinger, Christine E. Seidman, Ibticem Raji, David-Alexandre Trégouët, Jean-Noël Trochu, Thomas Wichter, Jörg Callis, Alain van Mil, Jean-François Deleuze, Declan P. O'Regan, Xavier Jouven, Jin Li, Klaus Stark, Eric Villard, Stuart A. Cook, Hakon Hakonarson, Michael Morley, Kenneth B. Marguiles, Sanjay K Prasad, Volker Ruppert, Jean-François Aupetit, Jean-Philippe Empana, Marcus Dörr, Thomas P. Cappola, Michel Komajda, Magdalena Harakalova, Christian Hengstenberg, Hélène Blanché, Angélique Curjol, L. Duboscq-Bidot, Richard Isnard, Olivier Dubourg, and K Lehnert
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Genetics ,0303 health sciences ,education.field_of_study ,Population ,Genome-wide association study ,Dilated cardiomyopathy ,Locus (genetics) ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,Genome ,Genetic architecture ,03 medical and health sciences ,0302 clinical medicine ,medicine ,SNP ,education ,Gene ,030304 developmental biology - Abstract
SummaryWe present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% ± 8%.In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one.This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.
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- 2020
21. Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
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S. Weiss, David A. Tregouet, Laurent Fauchier, Xavier Jouven, Jean-François Deleuze, Sophie Garnier, Marcus Dörr, Magdalena Harakalova, Jean-Noël Trochu, Richard Dorent, P. De Groote, Michal Mokry, Eric Villard, Olivier Dubourg, P. Charron, François Cambien, Folkert W. Asselbergs, Michel Komajda, L. Duboscq-Bidot, and Richard Isnard
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Genetics ,Candidate gene ,education.field_of_study ,business.industry ,Population ,Locus (genetics) ,Single-nucleotide polymorphism ,Dilated cardiomyopathy ,Quantitative trait locus ,medicine.disease ,Genetic architecture ,Medicine ,SNP ,Cardiology and Cardiovascular Medicine ,business ,education - Abstract
Background Dilated cardiomyopathy (DCM) is a major cause of systolic heart failure and therefore a major public health issue. Purpose Our objective was to better understand the genetic bases of dilated cardiomyopathy. Methods We conducted a 1000G based genome-wide association study for 9,152,885 SNPs on 2,719 sporadic DCM cases and 4,440 controls of European origin followed by a replication step. We then sought for the most likely culprit genes at the new replicated loci through a dedicated strategy including in silico data mining (including tissue specific gene expressions, expression and methylation quantitative trait loci) as well as functional 4C-sequencing analysis on iPSC-derived cardiomyocytes ( Fig. 1 ). Results We identified two new DCM loci, on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively) and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3, respectively), while confirming two previously identified ones, BAG3 and HSPB7. A Genetic Risk Score was built from the number of risk allele at these four loci and revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). At chr3p25, our selection strategy pinpointed SLC6A6 as the most likely culprit gene. SLC6A6 encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, the same strategy strongly suggested SMARCB1 as the best candidate gene. Conclusion This study provides new insights in the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective especially through taurine modulation.
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- 2021
22. Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans
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François Cambien, Johan Björkegren, Yuna Blum, Veronica Codoni, Wilfried Le Goff, Oscar Franzén, Mete Civelek, David-Alexandre Trégouët, Carole Proust, Aldons J. Lusis, HAL UPMC, Gestionnaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Virginia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Karolinska Institutet [Stockholm], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of California-University of California, and University of Virginia [Charlottesville]
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0301 basic medicine ,Genotype ,Ubiquitin-Protein Ligases ,Quantitative Trait Loci ,Gene regulatory network ,Regulator ,Investigations ,Biology ,QH426-470 ,Gene Expression Regulation, Enzymologic ,Oxidative Phosphorylation ,Workflow ,Evolution, Molecular ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Gene expression ,Genetics ,Animals ,Humans ,Macrophage ,Gene Regulatory Networks ,Molecular Biology ,Gene ,trans genetic effects ,Genetics (clinical) ,Gene knockdown ,Gene Expression Profiling ,cross-species comparison ,Computational Biology ,High-Throughput Nucleotide Sequencing ,gene expression network analysis ,macrophages ,Gene expression profiling ,030104 developmental biology ,Gene Expression Regulation ,eQTL analysis ,Expression quantitative trait loci ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Transcriptome ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Cardiogenics Consortium, IDEM Leducq Consortium CADGenomics; International audience; Macrophages are key players involved in numerous pathophysiological pathways and an in-depth characterization of their gene regulatory networks can help in better understanding how their dysfunction may impact on human diseases. We here conducted a cross-species network analysis of macrophage gene expression data between human and mouse to identify conserved networks across both species, and assessed whether such networks could reveal new disease-associated regulatory mechanisms. From a sample of 684 individuals processed for genome-wide macrophage gene expression profiling, we identified 27 groups of coexpressed genes (modules). Six modules were found preserved (P , 10 24) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 · 10 211 ] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR , 10 24) enriched in susceptibility genes for Alzheimer, Parkinson, and Huntington diseases. We further conducted an expression quantitative trait loci analysis to identify SNP that could regulate macrophage OXPHOS gene expression in humans. This analysis identified the PARK2 rs192804963 as a transacting variant influencing (minimal P-value = 4.3 · 10 28) the expression of most OXPHOS genes in humans. Further experimental work demonstrated that PARK2 knockdown expression was associated with increased OXPHOS gene expression in THP1 human macrophages. This work provided strong new evidence that PARK2 participates to the regulatory networks associated with oxidative phosphorylation and suggested that PARK2 genetic variations could act as a trans regulator of OXPHOS gene macrophage expression in humans.
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- 2016
23. Role of lipid phosphate phosphatase 3 in human aortic endothelial cell function
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Yuna Blum, Henri Weidmann, Mete Civelek, Aldons J. Lusis, Zahia Touat-Hamici, Veronica Codoni, Ewa Ninio, Pauline Gaignard, Carole Proust, Francesca Iannacci, Sonia Karabina, Patrice Therond, François Cambien, Hervé Durand, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Université Paris-Sud - Paris 11 (UP11), Service de Biochimie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Sante et de la Recherche Medicale and the Transatlantic Networks of Excellence, Fondation Leducq (12CVD02) (France)National Institutes of Health (USA) grants (HL28481 and K99HL121172), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), HAL-UPMC, Gestionnaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of California-University of California, Physiopathologie des maladies génétiques d'expression pédiatrique, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Physiology ,Angiogenesis ,medicine.medical_treatment ,Apoptosis ,Substrate Specificity ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Sphingosine ,Catalytic Domain ,Lysophosphatidic acid ,Endothelial dysfunction ,Aorta ,Cells, Cultured ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Cell biology ,Endothelial stem cell ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Cytokine ,030220 oncology & carcinogenesis ,Cytokines ,RNA Interference ,lipids (amino acids, peptides, and proteins) ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,Primary Cell Culture ,Phosphatidate Phosphatase ,Neovascularization, Physiologic ,Biology ,Transfection ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Protein Domains ,Physiology (medical) ,Cell Adhesion ,medicine ,Humans ,Cell adhesion ,Endothelial Cells ,Original Articles ,Atherosclerosis ,medicine.disease ,030104 developmental biology ,chemistry ,Mutation ,Lysophospholipids - Abstract
Aims Lipid phosphate phosphatase 3; type 2 phosphatidic acid phosphatase β (LPP3; PPAP2B ) is a transmembrane protein dephosphorylating and thereby terminating signalling of lipid substrates including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). Human LPP3 possesses a cell adhesion motif that allows interaction with integrins. A polymorphism (rs17114036) in PPAP2B is associated with coronary artery disease, which prompted us to investigate the possible role of LPP3 in human endothelial dysfunction, a condition promoting atherosclerosis. Methods and results To study the role of LPP3 in endothelial cells we used human primary aortic endothelial cells (HAECs) in which LPP3 was silenced or overexpressed using either wild type or mutated cDNA constructs. LPP3 silencing in HAECs enhanced secretion of inflammatory cytokines, leucocyte adhesion, cell survival, and migration and impaired angiogenesis, whereas wild-type LPP3 overexpression reversed these effects and induced apoptosis. We also demonstrated that LPP3 expression was negatively correlated with vascular endothelial growth factor expression. Mutations in either the catalytic or the arginine-glycine-aspartate (RGD) domains impaired endothelial cell function and pharmacological inhibition of S1P or LPA restored it. LPA was not secreted in HAECs under silencing or overexpressing LPP3. However, the intra- and extra-cellular levels of S1P tended to be correlated with LPP3 expression, indicating that S1P is probably degraded by LPP3. Conclusions We demonstrated that LPP3 is a negative regulator of inflammatory cytokines, leucocyte adhesion, cell survival, and migration in HAECs, suggesting a protective role of LPP3 against endothelial dysfunction in humans. Both the catalytic and the RGD functional domains were involved and S1P, but not LPA, might be the endogenous substrate of LPP3.
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- 2016
24. Genetic Reduction in Left Ventricular Protein Kinase C-alpha and Adverse Ventricular Remodeling in Human Subjects
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Thomas P. Cappola, Nathan R. Tucker, Ray Hu, Ramachandran S. Vasan, François Cambien, Janine F. Felix, Pim van der Harst, Cecilia E. Kim, Honghuang Lin, Victoria A. Parsons, W.H. Wilson Tang, Kenneth B. Margulies, Michael Morley, Christine S. Moravec, Nicholas L. Smith, Euan A. Ashley, Jin Li, Jeffrey Brandimarto, Marjorie Maillet, Hugo A. Katus, Benjamin Meder, Eric Villard, Patrick T. Ellinor, Sridhar Hannenhalli, Monika Stoll, Frank Rühle, Hakon Hakonarson, Sihai Dave Zhao, Jeffery D. Molkentin, Christopher Newton-Cheh, Epidemiology, and Cardiovascular Centre (CVC)
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Male ,0301 basic medicine ,Linkage disequilibrium ,heart failure ,Genome-wide association study ,030204 cardiovascular system & hematology ,ventricular remodeling ,Linkage Disequilibrium ,0302 clinical medicine ,Genes, Reporter ,ELECTROCARDIOGRAPHIC DETECTION ,genetics ,Zebrafish ,ENHANCES CARDIAC CONTRACTILITY ,Homozygote ,Heart ,Dilated cardiomyopathy ,General Medicine ,gene expression regulation ,Middle Aged ,HEART-FAILURE ,Female ,RUBOXISTAURIN ,Adult ,EXPRESSION ,medicine.medical_specialty ,Protein Kinase C-alpha ,Genotype ,Heart Ventricles ,Quantitative Trait Loci ,INHIBITION ,Biology ,Article ,PKC-BETA ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Allele ,GENOME-WIDE ASSOCIATION ,Ventricular remodeling ,Alleles ,Aged ,medicine.disease ,DILATED CARDIOMYOPATHY ,Introns ,Minor allele frequency ,030104 developmental biology ,Endocrinology ,Haplotypes ,MYOCARDIAL-INFARCTION ,Heart failure ,Expression quantitative trait loci ,protein kinase C - Abstract
Background: Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations. Methods and Results: We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, P =1×10 −41 ). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete ( R 2 =1.0) linkage disequilibrium with rs9912468 within intron 2 of PRKCA. We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The PRKCA enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α–lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α–lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations. Conclusions: These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.
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- 2018
25. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci
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Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)
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Netherlands Twin Register (NTR) ,Erythrocytes ,Genome-wide association study ,UNCERTAINTY ,Regulatory Sequences, Nucleic Acid ,VARIANTS ,ANNOTATION ,COLORECTAL-CANCER ,Histones ,0302 clinical medicine ,BINDING ,Cluster Analysis ,Myeloid Cells ,Genetics (clinical) ,Genetics ,hematological trait ,0303 health sciences ,Chromosome Mapping ,MRP4 ABCC4 ,Chromatin ,Nucleosomes ,Phenotype ,Organ Specificity ,030220 oncology & carcinogenesis ,Blood Platelets ,Quantitative Trait Loci ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,DYNAMIN 3 ,03 medical and health sciences ,Quantitative Trait, Heritable ,MEGAKARYOCYTES ,Humans ,Cell Lineage ,ddc:610 ,GENOME-WIDE ASSOCIATION ,Enhancer ,Transcription factor ,Gene ,ChIA-PET ,030304 developmental biology ,Research ,Genetic Variation ,DNA ,Chromatin Assembly and Disassembly ,Genetic architecture ,Gene Expression Regulation ,Genome-Wide Association Study - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510
- Published
- 2013
26. Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry
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Véronique Regnault, Pierre Boutouyrie, Pascal Challande, Frederique Thomas, Jean-Philippe Empana, Patrick Lacolley, Xavier Jouven, François Cambien, Zhenlin Li, Guillaume Escriou, Stéphane Laurent, B. Pannier, Maureen Alivon, Nicolas Danchin, Carole Proust, and Ulrike Esslinger
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Male ,Paris ,Candidate gene ,medicine.medical_specialty ,Pathology ,Genotype ,Monosaccharide Transport Proteins ,Carotid Artery, Common ,Genome-wide association study ,Coronary Artery Disease ,Biology ,Carotid Intima-Media Thickness ,Polymorphism, Single Nucleotide ,Vascular Stiffness ,Gene Frequency ,Polymorphism (computer science) ,medicine.artery ,Internal medicine ,Genetic variation ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Lectins, C-Type ,Prospective Studies ,Common carotid artery ,Allele frequency ,Triglycerides ,Genetics (clinical) ,Aged ,Cholesterol, HDL ,Genetic Variation ,Middle Aged ,Lipids ,Minor allele frequency ,Phenotype ,Endocrinology ,Female ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background— We assess the contribution of common and rare putatively functional genetic variants (most of them coding) present on the Illumina exome Beadchip to the variability of plasma lipids and stiffness of the common carotid artery. Methods and Results— Measurements were obtained from 2283 men and 1398 women, and after filtering and exclusion of monomorphic variants, 32 827 common (minor allele frequency >0.01) and 68 770 rare variants were analyzed. A large fraction of the heritability of plasma lipids is attributable to variants present on the array, especially for triglycerides (fraction of variance attributable to measured genotypes: V (G)/ V p =31.4%, P –11 ) and high-density lipoprotein cholesterol ( V (G)/ V p =26.4%, P –12 ). Plasma lipids were associated with common variants located in known candidate genes, but no implication of rare variants could be established. Gene sets for plasma lipids, blood pressure, and coronary artery disease were defined on the basis of recent meta-analyses of genome-wide association studies. We observed a strong association between the plasma lipids gene set and plasma lipid variables, but none of the 3 genome-wide association studies gene sets was associated with the carotid parameters. Significant V (G)/ V p ratios were observed for external (14.5%, P –5 ) and internal diameter (13.4%, P –4 ), stiffness (12.5%, P –4 ), intima-media thickness (10.6%, P –4 ), and wall cross-sectional area (13.2%, P –5 ). A significant association was observed between the common rs2903692 polymorphism of the CLEC16A gene and the internal diameter ( P –7 ). Conclusions— These results suggest an involvement of CLEC16A , a gene that has been reported to be associated with immune disorders, in the modulation of carotid vasodilatation.
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- 2015
27. Exome-wide Association Study Reveals Novel Susceptibility Genes to Sporadic Dilated Cardiomyopathy
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Xavier Jouven, Eric Villard, Jean Philippe Empana, Sophie Garnier, François Cambien, Michel Komajda, Richard Isnard, Patrick Lacolley, Claudine Perret, Carole Proust, Ulrike B. Esslinger, Agathe Korniat, Pierre Boutouyrie, Philippe Charron, David-Alexandre Trégouët, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), INSERM U652, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Dpt Cardiologie [CHU Georges Pompidou], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
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Genetics ,Candidate gene ,business.industry ,[SDV]Life Sciences [q-bio] ,Susceptibility gene ,Dilated cardiomyopathy ,musculoskeletal system ,medicine.disease ,complex mixtures ,Penetrance ,Proteostasis ,cardiovascular system ,Medicine ,Missense mutation ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,business ,Exome ,Gene - Abstract
Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results Overall, 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value Conclusion We identified eight loci independently associated with sporadic DCM. Overlap between susceptibility gene and familial DCM causing gene suggests a continuum of effect size, or penetrance, in DCM associated molecular variants. The functions of the best candidate genes at these loci also suggest that proteostasis regulation might play a role in DCM pathophysiology.
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- 2017
28. Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy
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François Cambien, Leanne E. Felkin, Frank Rühle, Connie R. Bezzina, Benjamin Meder, Philippe Charron, Monika Stoll, Yigal M. Pinto, Hugo A. Katus, Norbert Hubner, Hanneke W. M. van Deutekom, Enrico Petretto, Paul J.R. Barton, Valentin Schneider, András Varró, Alfred L. George, Elisabeth M. Lodder, Cristobal G. dos Remedios, Carola Rintisch, Aida Moreno-Moral, Anja Bauerfeind, Stuart A. Cook, Nanette H. Bishopric, Sebastian Schafer, Franz Rüschendorf, Michiel E. Adriaens, Matthias Heinig, Eric Villard, Esther E. Creemers, Francesco Pesce, James S. Ware, Cardiology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Wellcome Trust, Fondation Leducq, Maastricht Centre for Systems Biology, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio, Cardiologie, Biochemie, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, and RS: CARIM - R1.01 - Blood proteins & engineering
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Male ,0301 basic medicine ,Candidate gene ,MYOCARDIAL ISCHEMIC-INJURY ,05 Environmental Sciences ,Cardiomyopathy ,Dilated cardiomyopathy ,Genome-wide association study ,Bioinformatics ,Dilated Cardiomyopathy ,Eqtl ,Gene Expression ,Genetics ,Heart ,lcsh:QH301-705.5 ,EXPRESSION VARIATION ,Genetics & Heredity ,MYOSIN HEAVY-CHAIN ,Middle Aged ,3. Good health ,LIGHT-CHAIN KINASE ,HEART-FAILURE ,Female ,FOLLISTATIN-LIKE 1 ,Life Sciences & Biomedicine ,Adult ,Cardiomyopathy, Dilated ,Genotype ,lcsh:QH426-470 ,Heart Ventricles ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Biology ,eQTL ,Polymorphism, Single Nucleotide ,MITOCHONDRIAL THIOREDOXIN REDUCTASE ,03 medical and health sciences ,Genetic variation ,medicine ,Humans ,GENOME-WIDE ASSOCIATION ,Alleles ,08 Information And Computing Sciences ,Science & Technology ,Research ,Myocardium ,Genetic Variation ,06 Biological Sciences ,medicine.disease ,NATRIURETIC-PEPTIDES ,Human genetics ,Alternative Splicing ,lcsh:Genetics ,030104 developmental biology ,Gene Expression Regulation ,lcsh:Biology (General) ,Biotechnology & Applied Microbiology ,Cardiovascular and Metabolic Diseases ,Expression quantitative trait loci ,ATRIAL-FIBRILLATION ,Gene expression ,Transcriptome ,Genome-Wide Association Study - Abstract
Background Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. Results Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. Conclusions RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1286-z) contains supplementary material, which is available to authorized users.
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- 2017
29. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
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Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. Scott, Mika Kähönen, Peter Schwarz, Psychiatry, EMGO - Mental health, Pattaro, Cristian, Teumer, Alexander, Gorski, Mathia, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthia, Foster, Meredith, Yang, Qiong, Chen, Ming Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abba, D'Adamo, ADAMO PIO, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., Van Der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andre, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, Van Duijn, Cornelia M., Saint Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Dougla, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H. 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H., Zelenika, Diana, Zhai, Guangju, Zhang, Weihua, Zhang, Feng, Zhao, Jing Hua, Zhu, Haidong, Zhu, Xiaofeng, Zitting, Paavo, Zukowska Szczechowska, Ewa, Okada, Yukinori, Wu, Jer Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su Chi, Wong, Tien Yin, Liu, Jianjun, Young, Terri L., Aung, Tin, Teo, Yik Ying, Kim, Young Jin, Kang, Daehee, Chen, Chien Hsiun, Tsai, Fuu Jen, Chang, Li Ching, Fann, S. J. Cathy, Mei, Hao, Hixson, James E., Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Albrecht, Eva, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan Tsong, Tanaka, Toshihiro, Reilly, Muredach P., Schunkert, Heribert, Assimes, Themistocles L., Hall, Alistair, Hengstenberg, Christian, König, Inke R., Laaksonen, Reijo, Mcpherson, Ruth, Thompson, John R., Thorsteinsdottir, Unnur, Ziegler, Andrea, Absher, Devin, Chen, Li, Cupples, L. Adrienne, Halperin, Eran, Li, Mingyao, Musunuru, Kiran, Preuss, Michael, Schillert, Arne, Thorleifsson, Gudmar, Wells, George A., Holm, Hilma, Roberts, Robert, Stewart, Alexandre F. R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.
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0301 basic medicine ,Nephrology ,Genetics and Molecular Biology (all) ,estimated glomerular filtration rate ,estimated glomerular filtration rate, chronic kidney disease, genetic determinants ,General Physics and Astronomy ,Kidney development ,Genome-wide association study ,Biochemistry ,Settore MED/14 - NEFROLOGIA ,Renal Insufficiency ,Chronic ,Genetics ,AGEN Consortium ,ddc:616 ,education.field_of_study ,Kidney ,Stage renal-disease ,Multidisciplinary ,Genome-wide association ,CHARGe-Heart Failure Group ,Gene Expression Regulation ,Genome-Wide Association Study ,Genotype ,Humans ,Renal Insufficiency, Chronic ,Genetic Predisposition to Disease ,Biochemistry, Genetics and Molecular Biology (all) ,Chemistry (all) ,Physics and Astronomy (all) ,Metaanalysis ,Renal Insufficiency, Chronic/genetics ,Biological sciences ,Serum creatinine ,medicine.anatomical_structure ,Efficient ,Ronyons -- Fisiologia ,Hypertension ,ICBP Consortium ,Transmembrane transporter activity ,genetic association, loci, kidney function ,CARDIOGRAM ,Human ,medicine.medical_specialty ,Science ,Population ,Renal function ,ECHOGen Consortium ,Replication ,Biology ,Environment ,Research Support ,General Biochemistry, Genetics and Molecular Biology ,N.I.H ,genetic determinants ,03 medical and health sciences ,GENOME-WIDE ASSOCIATION ,FALSE DISCOVERY RATES ,STAGE RENAL-DISEASE ,SERUM CREATININE ,METAANALYSIS ,VARIANTS ,INDIVIDUALS ,POPULATION ,RISK ,HYPERTENSION ,Kidney function ,Research Support, N.I.H., Extramural ,Internal medicine ,MD Multidisciplinary ,medicine ,Journal Article ,eGFRcrea ,eGFRcys ,ddc:610 ,Genetik ,Mortality ,education ,ddc:613 ,urogenital system ,Individuals ,Extramural ,General Chemistry ,ta3121 ,medicine.disease ,R1 ,030104 developmental biology ,570 Life sciences ,biology ,Genètica ,chronic kidney disease ,Kidney disease ,Meta-Analysis - Abstract
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
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- 2016
30. Large-scale association analysis identifies new risk loci for coronary artery disease
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Benjamin F. Voight, Andrew D. Morris, G. Kees Hovingh, Anthony J. Balmforth, Hanneke Basart, Alistair S. Hall, Dominique Gauguier, Bok Ghee Han, Martina Müller-Nurasyid, Sarah Parish, Jarmo Virtamo, Christa Meisinger, Peter Wagner, George Dedoussis, Philipp S. Wild, Kari Stefansson, Jean-Baptiste Cazier, Kathleen Stirrups, Jiyoung Lee, Adrienne Cupples, Stavroula Kanoni, Danish Saleheen, Christian Hengstenberg, Svati H. Shah, Panos Deloukas, Anuj Goel, Stefan Blankenberg, Sian Tsung Tan, Alison H. Goodall, Tõnu Esko, Eric Boerwinkle, Gudmundur Thorgeirsson, Peter S. Braund, Joshua W. Knowles, Olle Melander, C. Ellen van der Schoot, Silke Rosinger, Maria Dimitriou, Wolfgang Koenig, Michael Boehnke, François Cambien, Per Lundmark, Dmitry Shungin, Wolfgang Kratzer, Pierre Zalloua, Reijo Laaksonen, Jean Ferrières, Villi Gudnason, Thorsten Kessler, Daniel J. Rader, Niclas Eriksson, Dominique Arveiler, Natalie R. van Zuydam, Kari Kuulasmaa, N. William Rayner, Sarah E. Hunt, Gudmar Thorleifsson, Jeanette Erdmann, Samuli Ripatti, Tsun-Po Yang, George A. Wells, Terho Lehtimäki, Kjell Nikus, Pierre Fontanillas, Jorg Hager, Martin Farrall, Jemma C. Hopewell, Frank Kee, Juha Sinisalo, Christopher J. O'Donnell, Asif Rasheed, Mika Kähönen, Genovefa Kolovou, Seraya Maouche, Suzanne Rafelt, Cordelia Langford, Winfried März, Leo-Pekka Lyytikäinen, Christina Willenborg, Weihua Zhang, Kati Kristiansson, Hyo-Soo Kim, Weang K. Ho, Jeong E. Park, Mohan U. Sivananthan, Moritz P. Rumpf, Markku Laakso, Klaus Stark, Philippe Amouyel, Paul W. Franks, Andres Metspalu, Anders Franco-Cereceda, Manjinder S. Sandhu, Nour Eddine El Mokhtari, Nicholas J. Wareham, Robert Roberts, Veikko Salomaa, Thomas Illig, Tomi Pastinen, Robert Clarke, Christof Burgdorf, Leif Groop, Devin Absher, Yangsoo Jang, Mark I. McCarthy, Bernhard O. Boehm, Per Eriksson, Nilesh J. Samani, Inke R. König, Stefan Schreiber, Karin Leander, Simone Claudi-Boehm, Ci Song, Benjamin A. Goldstein, Stephen E. Epstein, Andreas Ziegler, Stanley L. Hazen, Arne Schäfer, Elin Grundberg, Sekar Kathiresan, John R. Thompson, Unnur Thorsteinsdottir, Muredach P. Reilly, Heribert Schunkert, Rory Collins, Thomas Quertermous, Jong-Young Lee, John Danesh, John C. Chambers, Marco M Ferrario, Carlos Iribarren, Claudia Langenberg, Hilma Holm, Rona J. Strawbridge, Alan S. Go, Cristen J. Willer, Ron Do, Emmi Tikkanen, Abbas Dehghan, Evelin Mihailov, Lindsay L. Waite, Patrick Diemert, Willem H. Ouwehand, Eric E. Schadt, Diana Rubin, David Altshuler, Marcus E. Kleber, Markus Perola, Alexandre F.R. Stewart, Jaspal S. Kooner, Themistocles L. Assimes, Inês Barroso, Bruna Gigante, Göran Hallmans, Marja-Liisa Lokki, Aki S. Havulinna, Anders Hamsten, Agneta Siegbahn, Lasse Folkersen, Erik Ingelsson, Martina E. Zimmermann, Colin N. A. Palmer, Paolo Brambilla, Ann-Christine Syvänen, Alun Evans, Åsa Johansson, John F. Peden, Alex S. F. Doney, Hugh Watkins, Johanna Kuusisto, Anders Lundmark, David G. Cox, Hyun Min Kang, Lars Lind, Krista Fischer, Markku S. Nieminen, Annette Peters, Norman Klopp, Stefan Gustafsson, Lars Wallentin, Nancy L. Pedersen, David-Alexandre Trégouët, Ulf de Faire, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine
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Adult ,Asian Continental Ancestry Group ,Male ,Candidate gene ,BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA ,Population ,European Continental Ancestry Group ,Quantitative Trait Loci ,CAD ,Genome-wide association study ,Single-nucleotide polymorphism ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Biology ,Quantitative trait locus ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,White People ,coronary artery disease, risk loci ,Cell Line ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Risk Factors ,medicine ,Humans ,genetics ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,cardiovascular diseases ,Polymorphism ,education ,030304 developmental biology ,Genetic association ,Aged ,Genetics ,0303 health sciences ,education.field_of_study ,Adult, Aged, Asian Continental Ancestry Group, Cell Line, Coronary Artery Disease ,genetics, European Continental Ancestry Group ,genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism ,Single Nucleotide, Quantitative Trait Loci, Risk Factors ,Single Nucleotide ,Middle Aged ,medicine.disease ,3. Good health ,Female ,Genome-Wide Association Study - Abstract
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.
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- 2012
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31. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation
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Jens Baumert, Gerjan Navis, Shelly G. Smith, Peter J. Grant, Anders Hamsten, Frances M K Williams, Russell P. Tracy, James B. Meigs, Maria Grazia Franzosi, Angela M. Carter, François Cambien, Wiek H. van Gilst, Kent D. Taylor, Folkert W. Asselbergs, Marcus E. Kleber, Kurt Lohman, Scott M. Williams, Saonli Basu, Martina Müller-Nurasyid, Angela Silveira, Pim van der Harst, Rory Collins, Geoffrey H. Tofler, Lasse Folkersen, Wolfgang Koenig, Christa Meisinger, Christopher J. O'Donnell, Qiong Yang, Aaron R. Folsom, John C. Chambers, Muredach P. Reilly, Norman Klopp, Weihong Tang, Ming-Huei Chen, Mahir Karakas, Bernhard R. Winkelmann, John Danesh, Sekar Kathiresan, Tamara B. Harris, Tim D. Spector, Pierre-Emmanuel Morange, John F. Peden, Danish Saleheen, Jaspal S. Kooner, Ann-Christine Syvänen, David-Alexandre Trégouët, Winfried März, Bernhard O. Boehm, Robert Clarke, Tiphaine Oudot-Mellakh, Nicholas L. Smith, Vinh Truong, Mary Cushman, André G. Uitterlinden, Lewis C. Becker, Joshua C. Bis, Udo Seedorf, Bengt Sennblad, Anders Franco-Cereceda, Yongmei Liu, Elisabeth M. C. Schrijvers, Hugh Watkins, Barbara McKnight, Diane M. Becker, Jingzhong Ding, Nicole Soranzo, Bruce M. Psaty, Anuj Goel, Per Eriksson, Mohammad Arfan Ikram, Annette Peters, So-Youn Shin, Abbas Dehghan, Lisa R. Yanek, Albert Hofman, Jason H. Moore, Hans L. Hillege, Per Lundmark, Jie Huang, Günther Silbernagel, Jemma C. Hopewell, John Öhrvik, Nena Matijevic, Alison H. Goodall, Maria Sabater-Lleal, Josyf C. Mychaleckyj, Rona J. Strawbridge, Andrew D. Johnson, Radiology & Nuclear Medicine, Epidemiology, Neurology, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)
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Candidate gene ,Genome-wide association study ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,CIRCADIAN CLOCK ,PLASMINOGEN-ACTIVATOR INHIBITOR-1 ,Biochemistry ,TYPE-1 EXPRESSION ,Monocytes ,Thrombosis and Hemostasis ,Cohort Studies ,0302 clinical medicine ,Gene Frequency ,Genetics ,RISK ,0303 health sciences ,ARNTL Transcription Factors ,GENETIC-VARIATION ,Hematology ,LIM Domain Proteins ,3. Good health ,ARNTL ,CORONARY-ARTERY-DISEASE ,RNA Interference ,Proteasome Endopeptidase Complex ,SUSCEPTIBILITY LOCI ,Genotype ,Immunology ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Cell Line ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Meta-Analysis as Topic ,Cell Line, Tumor ,Plasminogen Activator Inhibitor 1 ,SNP ,Humans ,PLASMA-LEVELS ,Allele frequency ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Mucin-3 ,Gene Expression Profiling ,Cell Biology ,Molecular biology ,Gene expression profiling ,PPAR gamma ,MYOCARDIAL-INFARCTION ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,TISSUE ,ATPases Associated with Diverse Cellular Activities ,Genome-Wide Association Study ,Transcription Factors - Abstract
We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10−8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10−10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10−8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10−8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.
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- 2012
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32. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
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Alistair S. Hall, Heribert Schunkert, Veikko Salomaa, John Gallacher, Robert Clarke, Christopher P. Nelson, Dan Mellström, Adam S. Butterworth, Danish Saleheen, Lu Qi, Michael Boehnke, Åsa Tivesten, Hilma Holm, C. Ellen van der Schoot, Maristella Steri, Christopher J. O'Donnell, Daniel I. Chasman, Kristine H. Allin, Stephen Kaptoge, Demosthenes B. Panagiotakos, Arthur A. M. Wilde, Jacqueline C. M. Witteman, John J.P. Kastelein, Peter Willeit, S. Wassertheil-Smoller, Altan Onat, Magnus Karlsson, George Davey-Smith, Augusto Rendon, Jeanette Erdmann, Eric B. Rimm, Svetlana Adamovic, James F. Wilson, Russell P. Tracy, John-Olov Jansson, Johan Sundström, Anders Hamsten, Bruce M. Psaty, Mary Cushman, Nadeem Sarwar, Anthony G. Wilson, Anne Tybjærg-Hansen, Olivier Harari, Paul W. Franks, Paul I.W. de Bakker, Jussi Kauhanen, Paul M. Ridker, Ulf de Faire, Claes Ohlsson, Tamara B. Harris, Richard F. Gillum, Erik Ingelsson, Östen Ljunggren, Yoav Ben-Shlomo, Marcus E. Kleber, Jemma C. Hopewell, Themistocles L. Assimes, G. Neil Thomas, Vilmundur Gudnason, Børge G. Nordestgaard, Alison H. Goodall, John Gregson, David Reich, Patrik Wennberg, John C. Chambers, Jukka T. Salonen, Nilesh J. Samani, Mark Woodward, Emelia J. Benjamin, Daniel F. Freitag, Peter S. Braund, Daniel J. Rader, Wolfgang Koenig, David Melzer, Joseph Hung, Jaspal S. Kooner, Heather M. Stringham, Tom W. Meade, Hugh Watkins, Lyle G. Best, JoAnn E. Manson, Albert Hofman, Emanuele Di Angelantonio, Bernard Cantin, Willem H. Ouwehand, François Cambien, Folkert W. Asselbergs, Muredach P. Reilly, Pei Gao, Johann Willeit, John Danesh, Jonathan A. Shaffer, Donal Gorman, Lars Wilhelmsen, Mieke D. Trip, Philippe Amouyel, Epidemiology, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Vascular Medicine, Other departments, Human Genetics, APH - Amsterdam Public Health, and Epidemiology and Data Science
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Coronary Disease ,Disease ,030204 cardiovascular system & hematology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,SDG 3 - Good Health and Well-being ,Risk Factors ,Medicine ,Humans ,Interleukin 6 ,Allele frequency ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,C-reactive protein ,Genetic Variation ,Articles ,General Medicine ,Receptors, Interleukin-6 ,3. Good health ,Minor allele frequency ,Causality ,Immunology ,Interleukin-6 receptor ,biology.protein ,Biomarker (medicine) ,Inflammation Mediators ,business ,Signal Transduction - Abstract
Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
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- 2012
33. Influence of sex and genetic variability on expression of X-linked genes in human monocytes
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François Cambien, Silke Szymczak, Maxime Rotival, Stefan Blankenberg, Thomas Münzel, Vinh Truong, Arne Schillert, David-Alexandre Trégouët, Tanja Zeller, Andreas Ziegler, Raphaële Castagné, and Laurence Tiret
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Adult ,Male ,Transcription, Genetic ,Microarray ,Quantitative Trait Loci ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Monocytes ,X-inactivation ,Sex Factors ,Genes, X-Linked ,X Chromosome Inactivation ,Gene expression ,Genetics ,Humans ,Genetic variability ,Gene ,Aged ,Chromosomes, Human, X ,Autosome ,Calcium-Binding Proteins ,Gender ,Genetic Variation ,Middle Aged ,Expression Quantitative Trait Locus ,Expression quantitative trait loci ,Female ,Genome-Wide Association Study - Abstract
In humans, the fraction of X-linked genes with higher expression in females has been estimated to be 5% from microarray studies, a proportion lower than the 25% of genes thought to escape X inactivation. We analyzed 715 X-linked transcripts in circulating monocytes from 1,467 subjects and found an excess of female-biased transcripts on the X compared to autosomes (9.4% vs 5.5%, p −5 ). Among the genes not previously known to escape inactivation, the most significant one was EFHC2 whose 20% of variability was explained by sex. We also investigated cis expression quantitative trait loci (eQTLs) by analyzing 15,703 X-linked SNPs. The frequency and magnitude of X-linked cis eQTLs were quite similar in males and females. Few genes exhibited a stronger genetic effect in females than in males ( ARSD , DCX , POLA1 and ITM2A) . These genes would deserve further investigation since they may contribute to sex pathophysiological differences.
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- 2011
34. A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
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Juergen Schrezenmeir, Heidi Rossmann, Joshua C. Bis, Tanja Zeller, Heinz Erich Wichmann, Sandra Wilde, Jeanette Erdmann, Serkalem Demissie, Wibke Reinhard, Roberto Elosua, Arne Schillert, Vilmundur Gudnason, Albert Hofman, Sekar Kathiresan, Philipp S. Wild, Christoph Bickel, François Cambien, Stefan Schreiber, Mary Susan Burnett, Eric Boerwinkle, Klaus Stark, Nour Eddine El Mokthari, Stefan Blankenberg, Mingyao Li, Veikko Salomaa, Medea S. Eleftheriadis, Marcus E. Kleber, Dominique Arveiler, Alun Evans, Kaisa Silander, Jarmo Virtamo, Michael M. Hoffmann, Arne Schäfer, Andreas Ziegler, Patrick Diemert, Till Keller, Aaron R. Folsom, Peter S. Braund, Annette Peters, Karl J. Lackner, Nehal N. Mehta, Stephen M. Schwartz, Nilesh J. Samani, Inke R. König, Heribert Schunkert, Renate B. Schnabel, Jens Baumert, L. Adrienne Cupples, André G. Uitterlinden, Tamara B. Harris, Muredach P. Reilly, Per-Gunnar Wiklund, Hans J. Rupprecht, Maja Barbalić, Jaqueline C M Witteman, Frank Kee, Jean Ferrières, Edith Lubos, Hendrik B. Sager, David S. Siscovick, Liming Qu, Norman Klopp, Daniel J. Rader, Thomas Münzel, Joseph M. Devaney, Hakon Hakonarson, Benjamin F. Voight, Stephen E. Epstein, Emmanuelle Yon, Albert V. Smith, Silke Szymczak, Claire Perret, Christoph Sinning, Diana Rubin, Maryam Kavousi, David Altshuler, Laurence Tiret, Carole Proust, Christopher J. O'Donnell, John R. Thompson, Winfried März, Olli Saarela, Arne Deiseroth, Thomas Illig, Philippe Amouyel, Christian Hengstenberg, Olle Melander, Kari Kuulasmaa, Alistair S. Hall, Epidemiology, and Internal Medicine
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Genomics ,Genome-wide association study ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Biology ,Polymorphism, Single Nucleotide ,Article ,Monocytes ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Genetic variation ,medicine ,Genetics ,coronary artery disease ,genome-wide association studies ,gene expression ,genetic variation ,genomics ,eQTL ,eSNP ,LIPA ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,RNA, Messenger ,Gene ,Genetics (clinical) ,030304 developmental biology ,Genetic association ,0303 health sciences ,Chromosomes, Human, Pair 10 ,Gene Expression Profiling ,Genetic Variation ,Sterol Esterase ,medicine.disease ,Gene expression profiling ,Case-Control Studies ,Expression quantitative trait loci ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background— eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results— In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P −3 . Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene ( P =3.7×10 −8 ; odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript ( P =1.3×10 −96 ). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function ( P =4.4×10 −3 ). Conclusions— The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA , located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
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- 2011
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35. Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease
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François Cambien, Markus Loeffler, Arif B. Ekici, Jeanette Erdmann, Christian Gieger, Iris M. Heid, Christian Hengstenberg, Klaus Stark, Markus Scholz, Karl Werdan, Arne Schäfer, Uta Ceglarek, Gert Matthes, Alistair S. Hall, Thomas Meitinger, Heribert Schunkert, Peter Lichtner, Dominik Huster, Alexander Kluttig, Thomas Illig, Frank Beutner, Daniel Teupser, Stefan Schreiber, Lesca M. Holdt, Nilesh J. Samani, Inke R. König, Karin Halina Greiser, Christoph D. Garlichs, H.-Erich Wichmann, Dorette Raaz-Schrauder, Nour Eddine El Mokhtari, Anika Großhennig, Alexander Benedikt Leichtle, Ronny Baber, Patrick Linsel-Nitschke, Wolfgang Wilfert, Peter S. Braund, André Reis, Christian Wittekind, Stephan Gielen, Diana Rubin, Georg Martin Fiedler, Laurence Tiret, and Joachim Thiery
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Male ,medicine.medical_specialty ,Lipoproteins ,Campesterol ,Population ,Genome-wide association study ,Single-nucleotide polymorphism ,Coronary Artery Disease ,Validation Studies as Topic ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,ABO Blood-Group System ,chemistry.chemical_compound ,Meta-Analysis as Topic ,Risk Factors ,Internal medicine ,ABO blood group system ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,ATP Binding Cassette Transporter, Subfamily G, Member 5 ,Allele ,education ,Genetic Association Studies ,Genetics (clinical) ,education.field_of_study ,ATP Binding Cassette Transporter, Subfamily G, Member 8 ,Case-control study ,Phytosterols ,Odds ratio ,Metabolism ,Endocrinology ,chemistry ,Case-Control Studies ,ATP-Binding Cassette Transporters ,Female ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background— Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). Methods and Results— A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P =1.6×10 −50 and 6.2×10 −25 , respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression ( P =0.009). Effects at the ABO locus were related to SNP rs657152 (combined P =9.4×10 −13 ). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P =2.2×10 −6 ; rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P =9.4×10 −6 ), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P =1.3×10 −5 ). Conclusion— Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.
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- 2010
36. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling
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Kristell Wanherdrick, Sonia-Athina Karabina, Gérard Lambeau, Rajai Atout, Ewa Ninio, Seraya Maouche, François Cambien, Sarah Gora, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (... - 2019) (UNS)
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Umbilical Veins ,Cytoskeleton organization ,p38 mitogen-activated protein kinases ,Blotting, Western ,Eukaryotic Initiation Factor-2 ,Fluorescent Antibody Technique ,Inflammation ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Protein Serine-Threonine Kinases ,030204 cardiovascular system & hematology ,Biology ,Endoplasmic Reticulum ,Biochemistry ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Endoribonucleases ,Genetics ,medicine ,Humans ,Gene Silencing ,Phospholipases A2, Secretory ,Molecular Biology ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,0303 health sciences ,Interleukin-6 ,Reverse Transcriptase Polymerase Chain Reaction ,ATF6 ,Endoplasmic reticulum ,Interleukin-8 ,Endothelial Cells ,Activating Transcription Factor 6 ,3. Good health ,Cell biology ,Lipoproteins, LDL ,Endothelial stem cell ,Unfolded Protein Response ,Unfolded protein response ,medicine.symptom ,Signal Transduction ,Biotechnology - Abstract
International audience; Secreted phospholipases A2 (sPLA2s) are present in atherosclerotic plaques and are now considered novel attractive therapeutic targets and potential biomarkers as they contribute to the development of atherosclerosis through lipoprotein-dependent and independent mechanisms. We have previously shown that hGX-sPLA2-phospholipolyzed LDL (LDL-X) induces proinflammatory responses in human umbilical endothelial cells (HUVECs); here we explore the molecular mechanisms involved. Global transcriptional gene expression profiling of the response of endothelial cells exposed to either LDL or LDL-X revealed that LDL-X activates multiple distinct cellular pathways including the unfolded protein response (UPR). Mechanistic insight showed that LDL-X activates UPR through calcium depletion of intracellular stores, which in turn disturbs cytoskeleton organization. Treatment of HUVECs and aortic endothelial cells (HAECs) with LDL-X led to activation of all 3 proximal initiators of UPR: eIF-2alpha, IRE1alpha, and ATF6. In parallel, we observed a sustained phosphorylation of the p38 pathway resulting in the phosphorylation of AP-1 downstream targets. This was accompanied by significant production of the proinflammatory cytokines IL-6 and IL-8. Our study demonstrates that phospholipolyzed LDL uses a range of molecular pathways including UPR to initiate endothelial cell perturbation and thus provides an LDL oxidation-independent mechanism for the initiation of vascular inflammation in atherosclerosis.-Gora, S., Maouche, S., Atout, R., Wanherdrick, K., Lambeau, G., Cambien, F., Ninio, E., Karabina, S.-A. Phospholipolyzed LDL induces an inflammatory response in endothelial cells through endoplasmic reticulum stress signaling.
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- 2010
37. Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms
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Marcello Arca, François Cambien, Wiek H. van Gilst, Robin P. F. Dullaart, Michael J. Pencina, Shinji Yokoyama, Folkert W. Asselbergs, S. Matthijs Boekholdt, John F. Thompson, Aaron Isaacs, Jacqueline C.M. Witteman, Odette Poirer, Gerjan Navis, Pamela A. McCaskie, John E. Deanfield, Ian Ford, Aroon D. Hingorani, Viviane Nicaud, Carlo Gaudio, Nicholas J. Wareham, Bernhard Paulweber, Kay-Tee Khaw, Meena Kumari, Dirk J. van Veldhuisen, Lyle J. Palmer, Naveed Sattar, Ramachandran S. Vasan, José V. Sorlí, Jose M. Ordovas, Sally L. Ricketts, Heikki Kauma, Benjamin D. Horne, Mika Kivimäki, Philippa J. Talmud, Fabiana Quagliarini, Juan P. Casas, Steve E. Humphries, Tina Shah, Reecha Sofat, Shah Ebrahim, A. Sandhofer, John J.P. Kastelein, Dilys J. Freeman, Kenji Okumura, Jackie A. Cooper, Debbie A Lawlor, Tricia Li, Liam Smeeth, Cornelia M. van Duijn, Chris J. Packard, Akimoto Goto, Sakari Kakko, Pim van der Harst, Manjinder S. Sandhu, Ralph B. D'Agostino, Michael Marmot, Y. Antero Kesäniemi, Vilmundur Gudnason, Valerie McCormack, Markku J. Savolainen, George Davey Smith, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, and Epidemiology
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high-density lipoproteins ,Epidemiology ,BLOOD-PRESSURE ,Pharmacology ,DISEASE ,chemistry.chemical_compound ,DOUBLE-BLIND ,High-density lipoprotein ,CIENCIAS MÉDICAS ::Medicina interna [UNESCO] ,Polymorphism (computer science) ,Physiology (medical) ,Cholesterylester transfer protein ,Genetics ,Medicine ,genetics ,High-density lipoproteins ,GENOME-WIDE ASSOCIATION ,UNESCO::CIENCIAS MÉDICAS ::Medicina interna ,HDL CHOLESTEROL ,biology ,business.industry ,Cholesterol ,Torcetrapib ,CIENCIAS MÉDICAS [UNESCO] ,Dose–response relationship ,Blood pressure ,chemistry ,ATHEROSCLEROSIS ,UNESCO::CIENCIAS MÉDICAS ,biology.protein ,MENDELIAN RANDOMIZATION ,epidemiology ,pharmacology ,lipids (amino acids, peptides, and proteins) ,TORCETRAPIB ,Cardiology and Cardiovascular Medicine ,business ,HIGH-DENSITY-LIPOPROTEIN ,LIPID-LEVELS ,Lipoprotein - Abstract
Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI −0.28 to 0.60 mm Hg) and diastolic blood pressure (−0.04 mm Hg, 95% CI −0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.
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- 2010
38. Matrix metalloproteinase-3 and intracranial arterial dolichoectasia
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François Cambien, Pierre Amarenco, Joëlle Benessiano, Pierre-Jean Touboul, Nadem Soufir, Marie-Paule Jacob, Bernard Grandchamp, Jean-Baptiste Michel, Julien Labreuche, and Fernando Pico
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Adult ,Brain Infarction ,Male ,medicine.medical_specialty ,Pathology ,Genotype ,Polymorphism (computer science) ,Ectasia ,Internal medicine ,Confidence Intervals ,Odds Ratio ,medicine ,Humans ,Genetic Predisposition to Disease ,Promoter Regions, Genetic ,Aged ,Polymorphism, Genetic ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,Odds ratio ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Matrix Metalloproteinases ,Abdominal aortic aneurysm ,Confidence interval ,Coronary arteries ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Neurology ,Cohort ,Cardiology ,Matrix Metalloproteinase 2 ,Female ,Matrix Metalloproteinase 3 ,Cerebral Arterial Diseases ,Neurology (clinical) ,business - Abstract
Objective Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is defined as an increase in length and diameter of intracranial arteries. Abdominal aortic aneurysm and ectasia of coronary arteries have been reported in association with IADE. In both conditions, a dysfunction of matrix metalloproteinases (MMP)-2, -3, and -9 have been found. Our aim was to investigate these MMP pathways in stroke patients with IADE. Methods Five hundred ten Caucasians patients with brain infarction were consecutively recruited at 12 centers. The diagnosis of IADE was made by consensus between 2 neurologists based on magnetic resonance imaging scans. Determination of MMP-2, -3, and -9 plasma levels was centralized in 1 laboratory. Because we found a threshold effect of MMP-3 plasma levels with the risk of IADE, determination of the MMP-3 5A/6A polymorphism was carried out. Results IADE was identified in 12% of stroke patients. There was no association of IADE with mean MMP-2, -3, and -9 plasma levels. After categorization of MMP plasma levels into tertiles, we found a higher risk of IADE with the lowest MMP-3 tertile (adjusted odds ratio [OR], 2.48; 95% confidence interval [CI], 1.17–5.23). In genotype analysis, there was a significant additive effect of the 5A allele on the risk of IADE, with an adjusted OR of 1.62 (95% CI, 1.03–2.55). Interpretation In this cohort of stroke patients of Caucasian ancestry, IADE was associated with low MMP-3 plasma levels and with the 5A/6A polymorphism of the promoter region of MMP-3. These results suggest that MMP-3 may play a role in IADE. ANN NEUROL 2010;67:508–515
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- 2009
39. Osteopontin gene variation and cardio/cerebrovascular disease phenotypes
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Viviane Nicaud, Julien Labreuche, Eva Brand, Caroline Morrison, Klaus Schmidt-Petersen, Alun Evans, Martin Paul, Marion Gautier-Bertrand, Alexis Elbaz, Claudia Hagedorn, Pierre Amarenco, Monika Stoll, Ralph Telgmann, François Cambien, Corinna Dördelmann, Dominique Arveiler, Jens W. Fischer, and Stefan-Martin Brand-Herrmann
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Brain Infarction ,Male ,Pathology ,medicine.medical_specialty ,Apolipoprotein B ,Myocardial Infarction ,Locus (genetics) ,030204 cardiovascular system & hematology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Cell Line, Tumor ,medicine ,Humans ,Osteopontin ,Allele ,Allele frequency ,Gene ,Aged ,Ultrasonography ,030304 developmental biology ,0303 health sciences ,Polymorphism, Genetic ,biology ,business.industry ,Promoter ,Middle Aged ,Molecular biology ,Blot ,Cerebrovascular Disorders ,Carotid Arteries ,Logistic Models ,Phenotype ,biology.protein ,Female ,Carrier Proteins ,Cardiology and Cardiovascular Medicine ,business - Abstract
We aimed at associating common osteopontin (OPN) gene variants with cardiovascular disease phenotypes.We scanned the OPN gene in 190 chromosomes from myocardial infarction (MI) patients and identified five variants in the promoter, three synonymous and one non-synonymous variant. All variants were investigated in case–control studies for MI (ECTIM: 990 cases, 900 controls) and brain infarction (BI) (GENIC: 466 cases, 444 controls). Promoter variants were functionally analyzed by bandshift assays, the coding D147D [T/C] by Western blot. Allele D147D C was independently and significantly associated with lower apoB levels ( P =0.044 [ECTIM] P =0.03 [GENIC]), its allele frequency was significantly lower in patients with BI compared to controls (OR [95% CI] 0.39 [0.20–0.74], P =0.004), and C allele carriers had a significantly lower frequency of presence of carotid plaques ( P =0.02). Bandshifts with HepG2 and Ea.hy926 nuclear proteins did not reveal any functionality of promoter variants, whereas the OPN-441C-containing construct resulted in reduced OPN protein expression in Western blots, complying with its potential protective effect on the phenotypes studied.We here provide evidence that a portion of the OPN locus is likely to associate with cardiovascular disease-related phenotypes. However, further experiments are warranted to clarify the functional role of OPN variants.
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- 2009
40. Association of three polymorphisms selected from a genome-wide association study with coronary heart disease in the Tunisian population
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Viviane Nicaud, Nesrine Abboud, Ali Ben Khalfallah, Touhami Mahjoub, François Cambien, Lakhdar Ghazouani, Wassim Youssef Alamawi, Sonia Ben Hadj Khalifa, and Claire Perret
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Male ,medicine.medical_specialty ,Tunisia ,Genotype ,Coronary Disease ,Genome-wide association study ,Locus (genetics) ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Formate-Tetrahydrofolate Ligase ,Aminohydrolases ,Multienzyme Complexes ,Internal medicine ,Genetic predisposition ,Humans ,Medicine ,Myocardial infarction ,Allele frequency ,Aged ,Genetic association ,Methylenetetrahydrofolate Dehydrogenase (NADP) ,Genetics ,Genome ,business.industry ,Hematology ,Middle Aged ,medicine.disease ,Case-Control Studies ,Chromosomes, Human, Pair 2 ,Female ,Chromosomes, Human, Pair 9 ,Cardiology and Cardiovascular Medicine ,business ,Genome-Wide Association Study - Abstract
Despite extensive exploration of many genes, strong evidence of a molecular genetic association with coronary heart disease (CHD) or myocardial infarction (MI) remains to be obtained. Recently, significant interest has emerged in mapping genetic susceptibility for complex traits through whole-genome studies association generating promoting data that will determine the genetic contribution to common human diseases such as coronary heart disease. The aim of the present case-control study including 324 healthy controls and 296 patients with coronary heart disease from Tunisia, was to assess relation between three polymorphisms previously reported to be strongly associated with coronary heart disease in the Welcome Trust Case Control Consortium (WTCCC) and the German myocardial infarction family studies: locus 9p21.3 (rs 1333049), locus 6q25.1 (rs6922269) and 2q36.3 (rs2943634). By single locus analysis, no differences in genotype distribution and allelic frequency were found between the two groups of study. The risk allele (C) for rs2943634 was less frequent among Tunisian population than in controls from the WTCCC and German studies (57% vs 65%). The three SNPs previously reported to be associated with CHD were not replicated in our small sample.
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- 2009
41. P-selectin gene polymorphisms and risk of coronary heart disease among Tunisians
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Touhami Mahjoub, Wassim Y. Almawi, Claire Perret, François Cambien, Sonia Bel-Hadj Khlifa, Lakhdar Ghazouani, Nesrine Abboud, and Viviane Nicaud
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Male ,Risk ,Linkage disequilibrium ,Tunisia ,Population ,Coronary Disease ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Gene Frequency ,Genotype ,Humans ,Medicine ,Genetic Predisposition to Disease ,cardiovascular diseases ,education ,Allele frequency ,Aged ,Genetics ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,Haplotype ,Hematology ,Middle Aged ,Genotype frequency ,Minor allele frequency ,P-Selectin ,Case-Control Studies ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
P-selectin plays a key role in inflammation and atherosclerosis, and polymorphic variants of P-selectin were implicated in the pathogenesis of atherosclerotic and inflammatory changes, including coronary heart disease (CHD) in many ethnic groups. We investigated the contribution of P-selectin promoter (-2123C/G, -1969G/A) and exon (Ser290Asn, Asn562Asp, Thr715Pro) polymorphisms to CHD genetic susceptibility among 298 Tunisian CHD patients and 339 controls. Minor allele and genotype frequencies of the five P-selectin SNPs were comparable between patients and controls, except for -2123G/G genotype which was more frequent in cases. The 715Pro allele was present at lower frequency in Tunisians than in Europeans, and was not protective of CHD. Linkage disequilibrium was seen between -1969G/A, and both Ser290Asn and Asn562Asp. Five-loci haplotype analysis did not identify any CHD-protective or CHD-susceptible haplotypes. To our knowledge, this was the first case-control study to be performed on an Arab/North-African population, and demonstrates that none of the five P-selectin polymorphisms investigated influence CHD susceptibility in Tunisian Arabs.
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- 2008
42. The renin-angiotensin-aldosterone system in cerebral small vessel disease
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Fernando Pico, David A. Brenner, Pierre Amarenco, Philip Scheltens, François Cambien, Odette Poirier, Julien Labreuche, Neurology, and Neuroscience Campus Amsterdam 2008
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Male ,Aldosterone synthase ,medicine.medical_specialty ,Angiotensin receptor ,Genotype ,medicine.drug_class ,Population ,Peptidyl-Dipeptidase A ,Biology ,Receptor, Angiotensin, Type 2 ,Renin-Angiotensin System ,chemistry.chemical_compound ,Internal medicine ,Renin–angiotensin system ,Confidence Intervals ,Odds Ratio ,medicine ,Cytochrome P-450 CYP11B2 ,Humans ,education ,Aged ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,Polymorphism, Genetic ,Aldosterone ,Leukoaraiosis ,Angiotensin-converting enzyme ,Middle Aged ,Magnetic Resonance Imaging ,Cerebrovascular Disorders ,Endocrinology ,Neurology ,chemistry ,Mineralocorticoid ,biology.protein ,Female ,Neurology (clinical) - Abstract
Cerebral small vessel disease (SVD) appears on magnetic resonance imaging (MRI) as leukoaraiosis (LA), etat crible (EC), and multiple lacunar infarctions (MLI). Although the pathophysiology of SVD is poorly understood, there is evidence of a genetic contribution. We sought to analyze the influence of the reninangiotensin-aldosterone system (RAAS) on SVD in symptomatic patients from the Genetique de l’Infarctus Cerebral (GENIC) study, including RAAS polymorphisms and circulating angiotensin converting enzyme (ACE). Caucasian patients (n = 510) with acute brain infarction (BI) were recruited and MRIs were evaluated for SVD, including LA, EC, and MLI. We considered ACE levels and several polymorphisms, including ACE, angiotensinogen, aldosterone synthase CYP11B2, and angiotensin II receptor type I. Among the polymorphisms, there were marginal negative associations between aldosterone synthase CYP11B2 -344C against severe EC (adjusted OR, 0.57; 95 % CI, 0.31– 1.05) and severe LA (adjusted OR, 0.54; 95 % CI, 0.30–0.95), both considering -344C dominant. In addition, the frequency of -344C decreased with the number of SVD abnormalities (p = 0.016). Mean plasma ACE was elevated in patients with MLI, but not with LA or EC. The risk of MLI increased gradually with increasing plasma ACE (adjusted OR, 1.25; 95 % CI, 1.02–1.53). This exploratory study found no strong evidence for RAAS involvement in severe SVD in this population. The whole spectrum of SVD, including EC, MLI, and LA, can be considered as phenotypes for genetic studies.
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- 2008
43. Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery Disease
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Stefan Blankenberg, Alistair S. Hall, Ralph McGinnis, Peter S. Braund, Alison H. Goodall, Richard J. Dixon, Nilesh J. Samani, Inke R. König, Daniel F Schwarz, Christian Hengstenberg, Andrew Keniry, John R. Thompson, Jeanette Erdmann, François Cambien, Nour Eddine El Mokhtari, Stefan Schreiber, Massimo Mangino, Panos Deloukas, Willem H. Ouwehand, Klaus Stark, Pierre Ducimetière, Marcus Fischer, Laurence Tiret, Andreas Ziegler, Christa Meisinger, Henrike Liptau, H.-Erich Wichmann, Anika Götz, Helen Pollard, David-Alexandre Trégouët, Mohammed J. R. Ghori, Patrick Linsel-Nitschke, Heribert Schunkert, and Ludwig A. Hothorn
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Genetic Markers ,Male ,Oncology ,medicine.medical_specialty ,Genotype ,Locus (genetics) ,Single-nucleotide polymorphism ,Coronary Artery Disease ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,Coronary artery disease ,Risk Factors ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,SNP ,Prospective Studies ,Aged ,Repetitive Sequences, Nucleic Acid ,Genetic association ,business.industry ,Haplotype ,Case-control study ,Genetic Variation ,Odds ratio ,Middle Aged ,medicine.disease ,Case-Control Studies ,Female ,Chromosomes, Human, Pair 9 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background— Recently, genome-wide association studies identified variants on chromosome 9p21.3 as affecting the risk of coronary artery disease (CAD). We investigated the association of this locus with CAD in 7 case-control studies and undertook a meta-analysis. Methods and Results— A single-nucleotide polymorphism (SNP), rs1333049, representing the 9p21.3 locus, was genotyped in 7 case-control studies involving a total of 4645 patients with myocardial infarction or CAD and 5177 controls. The mode of inheritance was determined. In addition, in 5 of the 7 studies, we genotyped 3 additional SNPs to assess a risk-associated haplotype (ACAC). Finally, a meta-analysis of the present data and previously published samples was conducted. A limited fine mapping of the locus was performed. The risk allele (C) of the lead SNP, rs1333049, was uniformly associated with CAD in each study ( P P =0.0001). Haplotype analysis further suggested that this effect was not homogeneous across the haplotypic background (test for interaction, P =0.0079). An autosomal-additive mode of inheritance best explained the underlying association. The meta-analysis of the rs1333049 SNP in 12 004 cases and 28 949 controls increased the overall level of evidence for association with CAD to P =6.04×10 −10 (odds ratio, 1.24; 95% confidence interval, 1.20 to 1.29). Genotyping of 31 additional SNPs in the region identified several with a highly significant association with CAD, but none had predictive information beyond that of the rs1333049 SNP. Conclusion— This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD.
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- 2008
44. Thrombomodulin gene polymorphisms in brain infarction and mortality after stroke
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Jean-Marc, Olivot, Julien, Labreuche, Thomas, De Broucker, Odette, Poirier, François, Cambien, Martine, Aiach, and Pierre, Amarenco
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Adult ,Brain Infarction ,Male ,medicine.medical_specialty ,Time Factors ,Genotype ,Thrombomodulin ,DNA Mutational Analysis ,Central nervous system ,Infarction ,Linkage Disequilibrium ,Central nervous system disease ,Risk Factors ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Platelet ,Genetic Testing ,Stroke ,Aged ,Aged, 80 and over ,Polymorphism, Genetic ,business.industry ,Vascular disease ,Chromosome Mapping ,Middle Aged ,medicine.disease ,Survival Rate ,medicine.anatomical_structure ,Endocrinology ,Haplotypes ,Neurology ,Mutation ,Immunology ,cardiovascular system ,Female ,France ,Neurology (clinical) ,business ,Cell activation ,Follow-Up Studies - Abstract
Thrombomodulin is expressed at the surface of endothelial cells and controls thrombin generation and thrombin-induced platelets and vascular cell activation. Several thrombomodulin gene polymorphisms have been associated with coronary events and brain infarction. In a previous analysis from the Etude du Profil Génétique de l'Infarctus Cérébral (GENIC) study, we found that soluble thrombomodulin (sTM) concentration modulated the risk of and prognosis for brain infarction.In 474 brain infarction cases and 483 controls from the GENIC study, we investigated the relationship between three thrombomodulin gene polymorphisms (-1748G/C, -1208/-1209delTT, +1418C/T) and sTM levels, brain infarction risk and 5-year mortality after stroke.The three polymorphisms were in linkage disequilibrium and defined three major haplotypes with no influence on sTM concentration (all P values0.16). Single locus and haplotype analyses found no significant association with brain infarction, even when the analysis was restricted to individuals without a vascular history. After 5 years of follow-up, we found no relationship with vascular or total mortality (all P values0.64).Our results suggest that these three thrombomodulin gene polymorphisms do not contribute to sTM level variations and are not associated with risk of brain infarction and mortality after stroke.
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- 2008
45. Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: the MORGAM Project
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Marie-Lise, Grisoni, Carole, Proust, Mervi, Alanne, Maylis, DeSuremain, Veikko, Salomaa, Kari, Kuulasmaa, François, Cambien, Viviane, Nicaud, Birgitta, Stegmayr, Jarmo, Virtamo, Denis, Shields, Frank, Kee, Laurence, Tiret, Alun, Evans, David-Alexandre, Tregouet, and K, Asplund
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Single-nucleotide polymorphism ,Disease ,Biology ,01 natural sciences ,Polymorphism, Single Nucleotide ,Cohort Studies ,010104 statistics & probability ,03 medical and health sciences ,Genetic variation ,Genetics ,SNP ,Humans ,Genetics(clinical) ,Computer Simulation ,0101 mathematics ,Allele ,Genetics (clinical) ,030304 developmental biology ,Sequence Tagged Sites ,0303 health sciences ,Haplotype ,Smoking ,Interleukin-18 ,Odds ratio ,Tag SNP ,3. Good health ,Genetics, Population ,Haplotypes ,Cardiovascular Diseases ,Case-Control Studies ,Regression Analysis ,Genome-Wide Association Study - Abstract
Interleukin-18 (IL-18) is a key inflammatory molecule suspected of being involved in the etiology of cardiovascular diseases (CVD). Five single nucleotide polymorphisms (SNPs) capturing the common genetic variation of the IL-18 gene (tag SNPs) were genotyped in five European prospective CVD cohorts including 1933 cases and 1938 non-cases as part of the MORGAM Project. Not a single SNP was found associated with CVD. However, a significant (P=0.002) gene-smoking interaction was observed. In smokers, the -105T allele was more frequent in cases than in non-cases (0.29 vs 0.25) and associated with an increased risk of disease (odds ratio (OR)=1.25 (1.07-1.45), P=0.005), whereas the inverse relationship tended to be observed in non-smokers (OR=0.90 (0.78-1.02), P=0.131). The gene-smoking interaction was broadly homogenous across the cohorts and was also observed through haplotype analyses. In conclusion, using the concerted effort of several European prospective CVD cohorts, we are able to show that one IL-18 tag SNP interacts with smoking to modulate the risk of developing CVD.
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- 2008
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46. Genetics of Cardiovascular Diseases
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Laurence Tiret and François Cambien
- Subjects
medicine.medical_specialty ,Candidate gene ,Genotype ,Genetics, Medical ,Genomics ,Disease ,Environment ,Apolipoproteins E ,Ischemia ,Physiology (medical) ,Epidemiology ,medicine ,Humans ,Biomedicine ,Genetics ,Polymorphism, Genetic ,Framingham Risk Score ,Base Sequence ,Genome, Human ,business.industry ,Chromosome Mapping ,Genetic Variation ,Phenotype ,Cardiovascular Diseases ,Apolipoprotein B-100 ,Mutation ,Mutation (genetic algorithm) ,Cardiology and Cardiovascular Medicine ,Risk assessment ,business - Abstract
When the search for genes that predispose to cardiovascular diseases (CVD) started >20 years ago, it was anticipated that genetic polymorphisms might be analogous to the already known CVD risk factors and could be incorporated in a risk model such as the Framingham score1 to assess the risk of an individual and adopt preventive or therapeutic measures accordingly. However, despite years of intensive research, not a single genetic risk factor is used for risk assessment. The new strategy of genome-wide association (GWA) studies (for example, see http://www.wtccc. org.uk/) coupled with the availability of very large cohorts of patients2 is starting to reveal novel genetic factors that contribute to disease risk. Whether these variants will be clinically more useful than those that were derived from the study of candidate genes still needs to be demonstrated. As time passes, the interest for genetic research on common CVD moves progressively from the direct expectation of risk stratification to the more fundamental understanding of disease origins and pathophysiology and their indirect diagnostic and therapeutic implications. The objective of the present review is not to provide an exhaustive account of the numerous studies conducted on the genetics of CVD (eg, Arnett et al3), but to introduce a few basic notions required to understand the language of genetics and genomics (see Appendix) and illustrate with a limited number of examples the important insights provided by genetic research into the causes and mechanisms of CVD. We will also discuss the new GWA strategy and why this approach is likely to have a considerable impact on biomedicine and human disease understanding. Finally, we will try to explain the unsuccessful search for genetic markers of risk and why phenotypic biomarkers are likely to be clinically more useful. During the past decade, considerable progress has been achieved …
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- 2007
47. European rational approach for the genetics of diabetic complications EURAGEDIC: patient populations and strategy
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Gbenga Kazeem, David-Alexandre Trégouët, Roger D. Cox, Alexandre Thévard, Carol Forsblom, François Cambien, Dominique Gauguier, Samy Hadjadj, Nathalie Vionnet, Lise Tarnow, Michel Marre, Martin Farrall, Ivo Gut, Fumihiko Matsuda, Hans-Henrik Parving, Mark Lathrop, and Per-Henrik Groop
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Adult ,Male ,Candidate gene ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Nephropathy ,Diabetic nephropathy ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,Diabetic Nephropathies ,Transplantation ,Type 1 diabetes ,business.industry ,Middle Aged ,medicine.disease ,Diabetes Mellitus, Type 1 ,Endocrinology ,Nephrology ,Case-Control Studies ,Albuminuria ,Female ,medicine.symptom ,business ,Kidney disease - Abstract
BACKGROUND: Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems. METHODS: Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n=2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent-offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing. RESULTS: In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions. CONCLUSIONS: The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in Type 1 diabetic patients.
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- 2007
48. Neutrophil elastase gene variation and coronary heart disease
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Klaus Schmidt-Petersen, Jacqueline Schönfelder, François Cambien, Dominique Arveiler, Eva Brand, Alun Evans, Corinna Dördelmann, Katrin Beining, Frank Kee, Caroline Morrison, Martin Paul, Christina Rüssmann, Stefan-Martin Brand-Herrmann, Ralph Telgmann, and Viviane Nicaud
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Adult ,Male ,Genotype ,RNA Stability ,Myocardial Infarction ,Coronary Disease ,Cell Line ,Exon ,Polymorphism (computer science) ,Genetics ,Humans ,RNA, Messenger ,General Pharmacology, Toxicology and Pharmaceutics ,Allele ,Promoter Regions, Genetic ,Base Pairing ,Molecular Biology ,Gene ,Alleles ,Genetics (clinical) ,Sequence Deletion ,Reporter gene ,Polymorphism, Genetic ,Expression vector ,biology ,Haplotype ,Middle Aged ,Molecular biology ,Amino Acid Substitution ,Case-Control Studies ,Neutrophil elastase ,biology.protein ,Molecular Medicine ,Female ,Leukocyte Elastase - Abstract
Aims Identification and functional characterization of variants in the neutrophil elastase (ELA2) gene in cardiovascular disease. Methods From participants of the ECTIM (Etude Cas-Temoins sur l'infarctus du Myocarde) Study with myocardial infarction (Ml) 2082 chromosomes were genetically scanned; 990 patients with Ml and 904 controls were genotyped for the common polymorphisms G-761A and S173S (C4890A). Expression vectors for Ela2 variants were transiently transfected, followed by Northern and Western blot analyses. Promoter variants were analyzed by transfection/reporter gene assays. Results We identified 11 genetic variants, two in the 5'-flanking (G-761A, -852/del53bp), six in exons (R49H, N81N, G93V, S173S, D222Y, P228L) and three in introns (C+29/in3T, C+149/in3T, C+137/in4T). In Belfast, 4890A allele carriers had a risk for Ml with an odds ratio (OR) of 1.44 (95% Cl 1.12-1.86; P= 0.005), the OR for Ml associated with the - 761 G/-4890A haplotype with reference to -761G/-4890C amounting to 2.38 (95% Cl 1.23-4.57; P=0.01). Transcript or protein expression of both allelic constructs (4890A and 4890C) did not, however, differ. Conversely, transcriptional activity was significantly elevated (
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- 2007
49. Differential haplotypic expression of the interleukin-18 gene
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Hartmut Kleinert, François Cambien, Stefan Blankenberg, Tiphaine Godefroy, Odette Poirier, Laurence Tiret, and Sandrine Barbaux
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Untranslated region ,Polymorphism, Genetic ,Haplotype ,Interleukin-18 ,Biology ,Molecular biology ,Gene Expression Regulation ,Haplotypes ,Cardiovascular Diseases ,Polymorphism (computer science) ,Allelic Imbalance ,Gene expression ,Genetics ,Humans ,Interleukin 18 ,Prospective Studies ,Allele ,Gene ,Genetics (clinical) - Abstract
Interleukin 18 (IL-18) is suspected to play an important role in atherosclerosis and plaque vulnerability. We had previously shown that haplotypes combining two IL18 gene polymorphisms in complete linkage disequilibrium, C-105T (rs360717) in 5'-untranslated region (UTR) and A+183G (rs5744292) in 3'-UTR, were related to IL-18 circulating levels and cardiovascular outcome, the C(-105) G(+183) haplotype being associated with lower IL-18 levels and lower cardiovascular risk. This study was aimed at investigating the functional role of the two polymorphisms and their haplotypes on IL18 expression levels. Allelic imbalance experiments conducted in 24 and 20 subjects heterozygous for the C-105T and the A+183G polymorphisms did not detect any difference when subjects were considered as a whole (-0.009+/-0.044, P=0.85 and +0.114+/-0.082, P=0.18, respectively). However, when splitting individuals according to their haplo-genotype, the haplotype C(-105) G(+183) was associated with a lower expression level than C(-105) A(+183) (-0.287+/-0.076, P=0.005), but did not differ from T(-105) A(+183) (-0.138+/-0.083, P=0.13). The lower expression associated with C(-105) G(+183) was confirmed by real-time reverse transcription-PCR. Transfection of different haplotypic versions of the 3'-UTR did not show any difference in the expression of an upstream reporter gene. A 10-h study of the mRNA degradation kinetics by allelic imbalance with the A+183G polymorphism did not show any differential allelic degradation. In conclusion, the haplotype associated with lower IL-18 circulating concentrations and a lower cardiovascular risk was consistently associated with decreased IL18 expression levels, although the exact functional mechanisms remain to be elucidated.
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- 2007
50. Patterns of Alcohol Consumption and Cardiovascular Risk in Northern Ireland and France
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Annie Bingham, Gérald Luc, Michèle Montaye, Philippe Amouyel, Dominique Arveiler, Frédéric Fumeron, Bernadette Haas, Pierre Ducimetière, Pedro Marques-Vidal, François Cambien, Alan Evans, John D Yarnell, Jean-Bernard Ruidavets, Jean Ferrières, and Frank Kee
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Medicine(all) ,Consumption (economics) ,Epidemiology ,business.industry ,Public Health, Environmental and Occupational Health ,Physical health ,Northern ireland ,Coronary heart disease ,Medicine ,Risk factor ,business ,Beneficial effects ,Alcohol consumption ,Who monica ,Demography - Abstract
The PRIME Study was begun in 1991 and recruited 10,600 men aged 50 to 59 years in the WHO MONICA Project centers of Belfast, Lille, Strasbourg and Toulouse. Although drinkers in France and Northern Ireland consumed almost identical amounts, the pattern of consumption was different. In Northern Ireland beer and spirits were the staple beverages, whereas in France it was predominantly red wine; in France, 90% of men drank at least one unit per week versus 61% in Northern Ireland. Frenchmen drank evenly throughout the week, whereas in Northern Ireland two thirds of the consumption took place on Friday and Saturday nights. In the 5-year follow up of PRIME in France, the usual cardiovascular protective effect of increasing consumption (up to 45 units per week) was shown and the level of significance for trend in consumption was highly significant (p = 0.006); in Northern Ireland, this pattern was less consistent and did not attain significance. It remains a matter of conjecture whether in Northern Ireland the beneficial effects of alcohol consumption were annulled by a pattern of drinking that increases blood pressure, a well-established risk factor for heart disease, or whether the protection in France resulted from the consumption of wine along with food.
- Published
- 2007
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