Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

Nicholas L. Smith; Jennifer E. Huffman; David P. Strachan; Jie Huang; Abbas Dehghan; Stella Trompet; Lorna M. Lopez; So-Youn Shin; Jens Baumert; Veronique Vitart; Joshua C. Bis; Sarah H. Wild; Ann Rumley; Qiong Yang; Andre G. Uitterlinden; David. J. Stott; Gail Davies; Angela M. Carter; Barbara Thorand; Ozren Polasek; Barbara McKnight; Harry Campbell; Alicja R. Rudnicka; Ming-Huei Chen; Brendan M. Buckley; Sarah E. Harris; Annette Peters; Drazen Pulanic; Thomas Lumley; Anton J. M. de Craen; David C. Liewald; Christian Gieger; Susan Campbell; Ian Ford; Alan J. Gow; Michelle Luciano; David J. Porteous; Xiuqing Guo; Naveed Sattar; Albert Tenesa; Mary Cushman; P. Eline Slagboom; Peter M. Visscher; Tim D. Spector; Thomas Illig; Igor Rudan; Edwin G. Bovill; Alan F. Wright; Wendy L. McArdle; Geoffrey Tofler; Albert Hofman; Rudi G. J. Westendorp; John M. Starr; Peter J. Grant; Mahir Karakas; Nicholas D. Hastie; Bruce M. Psaty; James F. Wilson; Gordon D. O. Lowe; Christopher J. O'Donnell; Jacqueline C. M. Witteman; J. Wouter Jukema; Ian J. Deary; Nicole Soranzo; Wolfgang Koenig; Caroline Hayward

doi:10.1161/CIRCULATIONAHA.110.009480

Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

Nicholas L. Smith^*, Jennifer E. Huffman, David P. Strachan, Jie Huang, Abbas Dehghan, Stella Trompet, Lorna M. Lopez, So-Youn Shin, Jens Baumert, Veronique Vitart, Joshua C. Bis, Sarah H. Wild, Ann Rumley, Qiong Yang, Andre G. Uitterlinden, David. J. Stott, Gail Davies, Angela M. Carter, Barbara Thorand, Ozren PolasekBarbara McKnight, Harry Campbell, Alicja R. Rudnicka, Ming-Huei Chen, Brendan M. Buckley, Sarah E. Harris, Annette Peters, Drazen Pulanic, Thomas Lumley, Anton J. M. de Craen, David C. Liewald, Christian Gieger, Susan Campbell, Ian Ford, Alan J. Gow, Michelle Luciano, David J. Porteous, Xiuqing Guo, Naveed Sattar, Albert Tenesa, Mary Cushman, P. Eline Slagboom, Peter M. Visscher, Tim D. Spector, Thomas Illig, Igor Rudan, Edwin G. Bovill, Alan F. Wright, Wendy L. McArdle, Geoffrey Tofler, Albert Hofman, Rudi G. J. Westendorp, John M. Starr, Peter J. Grant, Mahir Karakas, Nicholas D. Hastie, Bruce M. Psaty, James F. Wilson, Gordon D. O. Lowe, Christopher J. O'Donnell, Jacqueline C. M. Witteman, J. Wouter Jukema, Ian J. Deary, Nicole Soranzo, Wolfgang Koenig, Caroline Hayward

^*Corresponding author for this work

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

53 Citations (Scopus)

Abstract

Background-Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

Methods and Results-A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between approximate to 2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log-transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4 x 10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4x10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9x10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log-transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

Conclusions-Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported. (Circulation. 2011;123:1864-1872.)

Original language	English
Pages (from-to)	1864-1872
Number of pages	17
Journal	Circulation
Volume	123
Issue number	17
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.110.009480
Publication status	Published - 3 May 2011

Keywords

RISK
MYOCARDIAL-INFARCTION
GENOME-WIDE ASSOCIATION
genome-wide association study
VON-WILLEBRAND-FACTOR
epidemiology
CORONARY HEART-DISEASE
meta-analysis
THR312ALA POLYMORPHISM
hemostasis
TISSUE-PLASMINOGEN ACTIVATOR
VENOUS THROMBOEMBOLISM
AGING RESEARCH
fibrin fragment D
thrombosis
CARDIOVASCULAR HEALTH

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10.1161/CIRCULATIONAHA.110.009480

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Smith, N. L., Huffman, J. E., Strachan, D. P., Huang, J., Dehghan, A., Trompet, S., Lopez, L. M., Shin, S.-Y., Baumert, J., Vitart, V., Bis, J. C., Wild, S. H., Rumley, A., Yang, Q., Uitterlinden, A. G., Stott, D. J., Davies, G., Carter, A. M., Thorand, B., ... Hayward, C. (2011). Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults. Circulation, 123(17), 1864-1872. https://doi.org/10.1161/CIRCULATIONAHA.110.009480

@article{39c932e981a24022803995ae71c41ea2,

title = "Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults",

abstract = "Background-Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.Methods and Results-A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between approximate to 2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log-transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4 x 10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4x10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9x10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log-transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.Conclusions-Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported. (Circulation. 2011;123:1864-1872.)",

keywords = "RISK, MYOCARDIAL-INFARCTION, GENOME-WIDE ASSOCIATION, genome-wide association study, VON-WILLEBRAND-FACTOR, epidemiology, CORONARY HEART-DISEASE, meta-analysis, THR312ALA POLYMORPHISM, hemostasis, TISSUE-PLASMINOGEN ACTIVATOR, VENOUS THROMBOEMBOLISM, AGING RESEARCH, fibrin fragment D, thrombosis, CARDIOVASCULAR HEALTH",

author = "Smith, {Nicholas L.} and Huffman, {Jennifer E.} and Strachan, {David P.} and Jie Huang and Abbas Dehghan and Stella Trompet and Lopez, {Lorna M.} and So-Youn Shin and Jens Baumert and Veronique Vitart and Bis, {Joshua C.} and Wild, {Sarah H.} and Ann Rumley and Qiong Yang and Uitterlinden, {Andre G.} and Stott, {David. J.} and Gail Davies and Carter, {Angela M.} and Barbara Thorand and Ozren Polasek and Barbara McKnight and Harry Campbell and Rudnicka, {Alicja R.} and Ming-Huei Chen and Buckley, {Brendan M.} and Harris, {Sarah E.} and Annette Peters and Drazen Pulanic and Thomas Lumley and {de Craen}, {Anton J. M.} and Liewald, {David C.} and Christian Gieger and Susan Campbell and Ian Ford and Gow, {Alan J.} and Michelle Luciano and Porteous, {David J.} and Xiuqing Guo and Naveed Sattar and Albert Tenesa and Mary Cushman and Slagboom, {P. Eline} and Visscher, {Peter M.} and Spector, {Tim D.} and Thomas Illig and Igor Rudan and Bovill, {Edwin G.} and Wright, {Alan F.} and McArdle, {Wendy L.} and Geoffrey Tofler and Albert Hofman and Westendorp, {Rudi G. J.} and Starr, {John M.} and Grant, {Peter J.} and Mahir Karakas and Hastie, {Nicholas D.} and Psaty, {Bruce M.} and Wilson, {James F.} and Lowe, {Gordon D. O.} and O'Donnell, {Christopher J.} and Witteman, {Jacqueline C. M.} and Jukema, {J. Wouter} and Deary, {Ian J.} and Nicole Soranzo and Wolfgang Koenig and Caroline Hayward",

year = "2011",

month = may,

day = "3",

doi = "10.1161/CIRCULATIONAHA.110.009480",

language = "English",

volume = "123",

pages = "1864--1872",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "17",

}

Smith, NL, Huffman, JE, Strachan, DP, Huang, J, Dehghan, A, Trompet, S, Lopez, LM, Shin, S-Y, Baumert, J, Vitart, V, Bis, JC, Wild, SH, Rumley, A, Yang, Q, Uitterlinden, AG, Stott, DJ, Davies, G, Carter, AM, Thorand, B, Polasek, O, McKnight, B, Campbell, H, Rudnicka, AR, Chen, M-H, Buckley, BM, Harris, SE, Peters, A, Pulanic, D, Lumley, T, de Craen, AJM, Liewald, DC, Gieger, C, Campbell, S, Ford, I, Gow, AJ, Luciano, M, Porteous, DJ, Guo, X, Sattar, N, Tenesa, A, Cushman, M, Slagboom, PE, Visscher, PM, Spector, TD, Illig, T, Rudan, I, Bovill, EG, Wright, AF, McArdle, WL, Tofler, G, Hofman, A, Westendorp, RGJ, Starr, JM, Grant, PJ, Karakas, M, Hastie, ND, Psaty, BM, Wilson, JF, Lowe, GDO, O'Donnell, CJ, Witteman, JCM, Jukema, JW, Deary, IJ, Soranzo, N, Koenig, W & Hayward, C 2011, 'Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults', Circulation, vol. 123, no. 17, pp. 1864-1872. https://doi.org/10.1161/CIRCULATIONAHA.110.009480

TY - JOUR

T1 - Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

AU - Smith, Nicholas L.

AU - Huffman, Jennifer E.

AU - Strachan, David P.

AU - Huang, Jie

AU - Dehghan, Abbas

AU - Trompet, Stella

AU - Lopez, Lorna M.

AU - Shin, So-Youn

AU - Baumert, Jens

AU - Vitart, Veronique

AU - Bis, Joshua C.

AU - Wild, Sarah H.

AU - Rumley, Ann

AU - Yang, Qiong

AU - Uitterlinden, Andre G.

AU - Stott, David. J.

AU - Davies, Gail

AU - Carter, Angela M.

AU - Thorand, Barbara

AU - Polasek, Ozren

AU - McKnight, Barbara

AU - Campbell, Harry

AU - Rudnicka, Alicja R.

AU - Chen, Ming-Huei

AU - Buckley, Brendan M.

AU - Harris, Sarah E.

AU - Peters, Annette

AU - Pulanic, Drazen

AU - Lumley, Thomas

AU - de Craen, Anton J. M.

AU - Liewald, David C.

AU - Gieger, Christian

AU - Campbell, Susan

AU - Ford, Ian

AU - Gow, Alan J.

AU - Luciano, Michelle

AU - Porteous, David J.

AU - Guo, Xiuqing

AU - Sattar, Naveed

AU - Tenesa, Albert

AU - Cushman, Mary

AU - Slagboom, P. Eline

AU - Visscher, Peter M.

AU - Spector, Tim D.

AU - Illig, Thomas

AU - Rudan, Igor

AU - Bovill, Edwin G.

AU - Wright, Alan F.

AU - McArdle, Wendy L.

AU - Tofler, Geoffrey

AU - Hofman, Albert

AU - Westendorp, Rudi G. J.

AU - Starr, John M.

AU - Grant, Peter J.

AU - Karakas, Mahir

AU - Hastie, Nicholas D.

AU - Psaty, Bruce M.

AU - Wilson, James F.

AU - Lowe, Gordon D. O.

AU - O'Donnell, Christopher J.

AU - Witteman, Jacqueline C. M.

AU - Jukema, J. Wouter

AU - Deary, Ian J.

AU - Soranzo, Nicole

AU - Koenig, Wolfgang

AU - Hayward, Caroline

PY - 2011/5/3

Y1 - 2011/5/3

N2 - Background-Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.Methods and Results-A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between approximate to 2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log-transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4 x 10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4x10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9x10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log-transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.Conclusions-Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported. (Circulation. 2011;123:1864-1872.)

AB - Background-Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.Methods and Results-A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between approximate to 2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log-transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4 x 10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4x10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9x10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log-transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.Conclusions-Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported. (Circulation. 2011;123:1864-1872.)

KW - RISK

KW - MYOCARDIAL-INFARCTION

KW - GENOME-WIDE ASSOCIATION

KW - genome-wide association study

KW - VON-WILLEBRAND-FACTOR

KW - epidemiology

KW - CORONARY HEART-DISEASE

KW - meta-analysis

KW - THR312ALA POLYMORPHISM

KW - hemostasis

KW - TISSUE-PLASMINOGEN ACTIVATOR

KW - VENOUS THROMBOEMBOLISM

KW - AGING RESEARCH

KW - fibrin fragment D

KW - thrombosis

KW - CARDIOVASCULAR HEALTH

U2 - 10.1161/CIRCULATIONAHA.110.009480

DO - 10.1161/CIRCULATIONAHA.110.009480

M3 - Article

C2 - 21502573

SN - 0009-7322

VL - 123

SP - 1864

EP - 1872

JO - Circulation

JF - Circulation

IS - 17

ER -

Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

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Keywords

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