Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.
Smith NL., Chen M-H., Dehghan A., Strachan DP., Basu S., Soranzo N., Hayward C., Rudan I., Sabater-Lleal M., Bis JC., de Maat MPM., Rumley A., Kong X., Yang Q., Williams FMK., Vitart V., Campbell H., Mälarstig A., Wiggins KL., Van Duijn CM., McArdle WL., Pankow JS., Johnson AD., Silveira A., McKnight B., Uitterlinden AG., Wellcome Trust Case Control Consortium; None., Aleksic N., Meigs JB., Peters A., Koenig W., Cushman M., Kathiresan S., Rotter JI., Bovill EG., Hofman A., Boerwinkle E., Tofler GH., Peden JF., Psaty BM., Leebeek F., Folsom AR., Larson MG., Spector TD., Wright AF., Wilson JF., Hamsten A., Lumley T., Witteman JCM., Tang W., O'Donnell CJ.
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 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-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 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-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.