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

TitleGene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.
Publication TypeJournal Article
Year of Publication2015
AuthorsTang W, Cushman M, Green D, Rich SS, Lange LA, Yang Q, Tracy RP, Tofler GH, Basu S, Wilson JG, Keating BJ, Weng L-C, Taylor HA, Jacobs DR, Delaney JA, Palmer CD, Young T, Pankow JS, O'Donnell CJ, Smith NL, Reiner AP
Secondary AuthorsFolsom AR
JournalAm J Hematol
Volume90
Issue6
Pagination534-40
Date Published2015 Jun
ISSN1096-8652
KeywordsAdult, African Americans, Aged, European Continental Ancestry Group, Factor VIII, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Methionine Adenosyltransferase, Middle Aged, Polymorphism, Single Nucleotide, Venous Thromboembolism, von Willebrand Factor
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.

DOI10.1002/ajh.24005
Alternate JournalAm J Hematol
PubMed ID25779970
PubMed Central IDPMC4747096
Grant ListN01 HC085086 / HC / NHLBI NIH HHS / United States
P30 AG024827 / AG / NIA NIH HHS / United States
HHSN268201300026C / HL / NHLBI NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
R01-HL59367 / HL / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
N01 HC095167 / HC / NHLBI NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01 HC075150 / HC / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL095603 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01 HC085083 / HC / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
N01 HC055018 / HC / NHLBI NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
N01 HC095161 / HC / NHLBI NIH HHS / United States
N01 HC065226 / HC / NHLBI NIH HHS / United States
N01 HC085085 / HC / NHLBI NIH HHS / United States
N01 HC095164 / HC / NHLBI NIH HHS / United States
N01 HC095166 / HC / NHLBI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
HHSN268201300025C / HL / NHLBI NIH HHS / United States
N01 HC095160 / HC / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
R01 DK055017 / DK / NIDDK NIH HHS / United States
N01 HC085082 / HC / NHLBI NIH HHS / United States
N01 HC055019 / HC / NHLBI NIH HHS / United States
N01 HC085080 / HC / NHLBI NIH HHS / United States
HHSN268201300027C / HL / NHLBI NIH HHS / United States
HHSN268200900041C / HL / NHLBI NIH HHS / United States
HHSN268201300028C / HL / NHLBI NIH HHS / United States
R01 AG032136 / AG / NIA NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
R01-HL095603 / HL / NHLBI NIH HHS / United States
N01 HC055015 / HC / NHLBI NIH HHS / United States
N01 HC055021 / HC / NHLBI NIH HHS / United States
N01 HC095165 / HC / NHLBI NIH HHS / United States
N01 HC085084 / HC / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
N01 HC055020 / HC / NHLBI NIH HHS / United States
N01 HC095163 / HC / NHLBI NIH HHS / United States
N01 HC085079 / HC / NHLBI NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
HHSN268201300029C / HL / NHLBI NIH HHS / United States
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