Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor

Author:

Smith Nicholas L.,Chen Ming-Huei,Dehghan Abbas,Strachan David P.,Basu Saonli,Soranzo Nicole,Hayward Caroline,Rudan Igor,Sabater-Lleal Maria,Bis Joshua C.,de Maat Moniek P.M.,Rumley Ann,Kong Xiaoxiao,Yang Qiong,Williams Frances M.K.,Vitart Veronique,Campbell Harry,Mälarstig Anders,Wiggins Kerri L.,Van Duijn Cornelia M.,McArdle Wendy L.,Pankow James S.,Johnson Andrew D.,Silveira Angela,McKnight Barbara,Uitterlinden Andre G.,Aleksic Nena,Meigs James B.,Peters Annette,Koenig Wolfgang,Cushman Mary,Kathiresan Sekar,Rotter Jerome I.,Bovill Edwin G.,Hofman Albert,Boerwinkle Eric,Tofler Geoffrey H.,Peden John F.,Psaty Bruce M.,Leebeek Frank,Folsom Aaron R.,Larson Martin G.,Spector Timothy D.,Wright Alan F.,Wilson James F.,Hamsten Anders,Lumley Thomas,Witteman Jacqueline C.M.,Tang Weihong,O'Donnell Christopher J.,

Abstract

Background— Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. Methods and Results— The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0×10 −8 and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2×10 −24 ), 4q25 (3.6×10 −12 ), 11q12 (2.0×10 −10 ), 13q34 (9.0×10 −259 ), and 20q11.2 (5.7×10 −37 ). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2×10 −22 ), 8p21 (1.3×10 −16 ), 9q34 (<5.0×10 −324 ), 12p13 (1.7×10 −32 ), 12q23 (7.3×10 −10 ), 12q24.3 (3.8×10 −11 ), 14q32 (2.3×10 −10 ), and 19p13.2 (1.3×10 −9 ). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. Conclusions— New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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