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; 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

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
, Joseph A. Delaney
, Cameron D. Palmer
, Taylor Young
, James S. Pankow
, Christopher J. O'Donnell
, Nicholas L. Smith

Alexander P. Reiner, Aaron R. Folsom

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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, 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 (P=1.69 × 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.

Original language	English (US)
Pages (from-to)	534-540
Number of pages	7
Journal	American Journal of Hematology
Volume	90
Issue number	6
DOIs	https://doi.org/10.1002/ajh.24005
State	Published - Jun 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Wiley Periodicals, Inc.

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Tang, W., Cushman, M., Green, D., Rich, S. S., Lange, L. A., Yang, Q., Tracy, R. P., Tofler, G. H., Basu, S., Wilson, J. G., Keating, B. J., Weng, L. C., Taylor, H. A., Jacobs, D. R., Delaney, J. A., Palmer, C. D., Young, T., Pankow, J. S., O'Donnell, C. J., ... Folsom, A. R. (2015). Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. American Journal of Hematology, 90(6), 534-540. https://doi.org/10.1002/ajh.24005

Tang, W, Cushman, M, Green, D, Rich, SS, Lange, LA, Yang, Q, Tracy, RP, Tofler, GH, Basu, S, Wilson, JG, Keating, BJ, Weng, LC, Taylor, HA, Jacobs, DR, Delaney, JA, Palmer, CD, Young, T, Pankow, JS, O'Donnell, CJ, Smith, NL, Reiner, AP & Folsom, AR 2015, 'Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans', American Journal of Hematology, vol. 90, no. 6, pp. 534-540. https://doi.org/10.1002/ajh.24005

@article{cfba83af796b4108ac36276c916c16c9,

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, 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 (P=1.69 × 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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 Wiley Periodicals, Inc.",

year = "2015",

month = jun,

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doi = "10.1002/ajh.24005",

language = "English (US)",

volume = "90",

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T1 - Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans

AU - Tang, Weihong

AU - Cushman, Mary

AU - Green, David

AU - Rich, Stephen S.

AU - Lange, Leslie A.

AU - Yang, Qiong

AU - Tracy, Russell P.

AU - Tofler, Geoffrey H.

AU - Basu, Saonli

AU - Wilson, James G.

AU - Keating, Brendan J.

AU - Weng, Lu Chen

AU - Taylor, Herman A.

AU - Jacobs, David R.

AU - Delaney, Joseph A.

AU - Palmer, Cameron D.

AU - Young, Taylor

AU - Pankow, James S.

AU - O'Donnell, Christopher J.

AU - Smith, Nicholas L.

AU - Reiner, Alexander P.

AU - Folsom, Aaron R.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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, 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 (P=1.69 × 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.

AB - 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, 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 (P=1.69 × 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.

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AN - SCOPUS:84929516608

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ER -

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

Abstract

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