title: Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.
abstract: Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Weihong
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of Vermont, Burlington, Vermont.|Department of Pathology, University of Vermont, Burlington, Vermont.
authors.forename: Mary
authors.initials: M
authors.lastname: Cushman
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine of Northwestern University, Chicago, Illinois.
authors.forename: David
authors.initials: D
authors.lastname: Green
authors.affiliation: Department of Public Health Sciences and the Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont.|Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.affiliation: Department of Cardiology, Royal North Shore Hospital, University of Sydney, Australia.
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Tofler
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Saonli
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Lu-Chen
authors.initials: LC
authors.lastname: Weng
authors.affiliation: Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: David R
authors.initials: DR
authors.lastname: Jacobs
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Delaney
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Cameron D
authors.initials: CD
authors.lastname: Palmer
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Taylor
authors.initials: T
authors.lastname: Young
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Department of Cardiovascular Epidemiology and Human Genomics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington.|Group Health Research Institute, Group Health Cooperative, Seattle, Washington.|Seattle Epidemiologic Research and Information Center, VA Office of Research and Development, Seattle, Washington.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Reiner
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Folsom
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008716:Methionine Adenosyltransferase / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054556:Venous Thromboembolism / Q000097:blood / Q000235:genetics; D044465:White People / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; C078147:F8 protein, human; D005169:Factor VIII; C506577:MAT1A protein, human; D008716:Methionine Adenosyltransferase