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Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

ABSTRACT: BACKGROUND:Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation. METHODS AND RESULTS:We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism. CONCLUSIONS:We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

SUBMITTER: Sabater-Lleal M

PROVIDER: S-EPMC3842025 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

Sabater-Lleal Maria M Huang Jie J Chasman Daniel D Naitza Silvia S Dehghan Abbas A Johnson Andrew D AD Teumer Alexander A Reiner Alex P AP Folkersen Lasse L Basu Saonli S Rudnicka Alicja R AR Trompet Stella S Mälarstig Anders A Baumert Jens J Bis Joshua C JC Guo Xiuqing X Hottenga Jouke J JJ Shin So-Youn SY Lopez Lorna M LM Lahti Jari J Tanaka Toshiko T Yanek Lisa R LR Oudot-Mellakh Tiphaine T Wilson James F JF Navarro Pau P Huffman Jennifer E JE Zemunik Tatijana T Redline Susan S Mehra Reena R Pulanic Drazen D Rudan Igor I Wright Alan F AF Kolcic Ivana I Polasek Ozren O Wild Sarah H SH Campbell Harry H Curb J David JD Wallace Robert R Liu Simin S Eaton Charles B CB Becker Diane M DM Becker Lewis C LC Bandinelli Stefania S Räikkönen Katri K Widen Elisabeth E Palotie Aarno A Fornage Myriam M Green David D Gross Myron M Davies Gail G Harris Sarah E SE Liewald David C DC Starr John M JM Williams Frances M K FM Grant Peter J PJ Spector Timothy D TD Strawbridge Rona J RJ Silveira Angela A Sennblad Bengt B Rivadeneira Fernando F Uitterlinden Andre G AG Franco Oscar H OH Hofman Albert A van Dongen Jenny J Willemsen Gonneke G Boomsma Dorret I DI Yao Jie J Swords Jenny Nancy N Haritunians Talin T McKnight Barbara B Lumley Thomas T Taylor Kent D KD Rotter Jerome I JI Psaty Bruce M BM Peters Annette A Gieger Christian C Illig Thomas T Grotevendt Anne A Homuth Georg G Völzke Henry H Kocher Thomas T Goel Anuj A Franzosi Maria Grazia MG Seedorf Udo U Clarke Robert R Steri Maristella M Tarasov Kirill V KV Sanna Serena S Schlessinger David D Stott David J DJ Sattar Naveed N Buckley Brendan M BM Rumley Ann A Lowe Gordon D GD McArdle Wendy L WL Chen Ming-Huei MH Tofler Geoffrey H GH Song Jaejoon J Boerwinkle Eric E Folsom Aaron R AR Rose Lynda M LM Franco-Cereceda Anders A Teichert Martina M Ikram M Arfan MA Mosley Thomas H TH Bevan Steve S Dichgans Martin M Rothwell Peter M PM Sudlow Cathie L M CL Hopewell Jemma C JC Chambers John C JC Saleheen Danish D Kooner Jaspal S JS Danesh John J Nelson Christopher P CP Erdmann Jeanette J Reilly Muredach P MP Kathiresan Sekar S Schunkert Heribert H Morange Pierre-Emmanuel PE Ferrucci Luigi L Eriksson Johan G JG Jacobs David D Deary Ian J IJ Soranzo Nicole N Witteman Jacqueline C M JC de Geus Eco J C EJ Tracy Russell P RP Hayward Caroline C Koenig Wolfgang W Cucca Francesco F Jukema J Wouter JW Eriksson Per P Seshadri Sudha S Markus Hugh S HS Watkins Hugh H Samani Nilesh J NJ Wallaschofski Henri H Smith Nicholas L NL Tregouet David D Ridker Paul M PM Tang Weihong W Strachan David P DP Hamsten Anders A O'Donnell Christopher J CJ

Circulation 20130822 12

<h4>Background</h4>Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2%) of its variation.<h4>Methods and results</h4>We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in ...[more]

PMID: 23969696

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Project description:Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics.We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Dataset Information

Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

Publications

Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.

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