Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans

Weihong Tang; Mary Cushman; David Green; Stephen S Rich; Leslie A Lange; Qiong Yang; Russell P Tracy; Geoffrey H Tofler; Saonli Basu; James G Wilson; Brendan J Keating; Lu-Chen Weng; Herman A Taylor; David R Jacobs Jr; Joseph A Delaney; Cameron D Palmer; Taylor Young; James S Pankow; Christopher J O'Donnell; Nicholas L Smith; Alexander P Reiner; Aaron R Folsom

doi:10.1002/ajh.24005

Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans

Am J Hematol. 2015 Jun;90(6):534-40. doi: 10.1002/ajh.24005. Epub 2015 Apr 1.

Authors

Weihong Tang¹, Mary Cushman^{2

3}, David Green⁴, Stephen S Rich⁵, Leslie A Lange⁶, Qiong Yang⁷, Russell P Tracy^{8

9}, Geoffrey H Tofler¹⁰, Saonli Basu¹¹, James G Wilson¹², Brendan J Keating¹³, Lu-Chen Weng¹, Herman A Taylor¹⁴, David R Jacobs Jr¹, Joseph A Delaney¹⁵, Cameron D Palmer¹⁶, Taylor Young¹⁶, James S Pankow¹, Christopher J O'Donnell¹⁷, Nicholas L Smith^{15

18

19}, Alexander P Reiner¹⁵, Aaron R Folsom¹

Affiliations

¹ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
² Department of Medicine, University of Vermont, Burlington, Vermont.
³ Department of Pathology, University of Vermont, Burlington, Vermont.
⁴ Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine of Northwestern University, Chicago, Illinois.
⁵ Department of Public Health Sciences and the Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
⁸ Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont.
⁹ Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont.
¹⁰ Department of Cardiology, Royal North Shore Hospital, University of Sydney, Australia.
¹¹ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
¹² Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
¹³ Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.
¹⁴ Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, Mississippi.
¹⁵ Department of Epidemiology, University of Washington, Seattle, Washington.
¹⁶ Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
¹⁷ Department of Cardiovascular Epidemiology and Human Genomics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
¹⁸ Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
¹⁹ Seattle Epidemiologic Research and Information Center, VA Office of Research and Development, Seattle, Washington.

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.

Publication types

Clinical Trial
Multicenter Study
Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Black or African American / genetics*
Factor VIII* / genetics
Factor VIII* / metabolism
Female
Genetic Loci
Genome-Wide Association Study
Humans
Male
Methionine Adenosyltransferase / blood
Methionine Adenosyltransferase / genetics
Middle Aged
Polymorphism, Single Nucleotide*
Venous Thromboembolism / blood
Venous Thromboembolism / genetics
White People / genetics*
von Willebrand Factor* / genetics
von Willebrand Factor* / metabolism

Substances

von Willebrand Factor
F8 protein, human
Factor VIII
MAT1A protein, human
Methionine Adenosyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding