Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

NL Smith; JE Huffman; DP Strachan; J Huang; Abbas Dehghan; S Trompet; LM Lopez; SY Shin; J Baumert; V Vitart; JC Bis; SH Wild; A Rumley; Q Yang; André Uitterlinden; DJ Stott; G Davies; AM Carter; B Thorand; O Polasek; B McKnight; H Campbell; AR Rudnicka; MH Chen; BM Buckley; SE Harris; A Peters; D Pulanic; T Lumley; AJM de Craen; DC Liewald; C Gieger; S Campbell; I Ford; AJ Gow; M Luciano; DJ Porteous; XQ Guo; N Sattar; A Tenesa; M Cushman; PE (Eline) Slagboom; PM Visscher; TD Spector; T Illig; I Rudan; EG Bovill; AF Wright; WL McArdle; G Tofler; Bert Hofman; RGJ Westendorp; JM Starr; PJ Grant; M Karakas; ND Hastie; BM Psaty; JF Wilson; GDO Lowe; CJ O'Donnell; JCM Witteman; JW Jukema; IJ Deary; N Soranzo; W Koenig; C Hayward

doi:10.1161/CIRCULATIONAHA.110.009480

Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

NL Smith, JE Huffman, DP Strachan, J Huang, Abbas Dehghan, S Trompet, LM Lopez, SY Shin, J Baumert, V Vitart, JC Bis, SH Wild, A Rumley, Q Yang, André Uitterlinden, DJ Stott, G Davies, AM Carter, B Thorand, O PolasekB McKnight, H Campbell, AR Rudnicka, MH Chen, BM Buckley, SE Harris, A Peters, D Pulanic, T Lumley, AJM de Craen, DC Liewald, C Gieger, S Campbell, I Ford, AJ Gow, M Luciano, DJ Porteous, XQ Guo, N Sattar, A Tenesa, M Cushman, PE (Eline) Slagboom, PM Visscher, TD Spector, T Illig, I Rudan, EG Bovill, AF Wright, WL McArdle, G Tofler, Bert Hofman, RGJ Westendorp, JM Starr, PJ Grant, M Karakas, ND Hastie, BM Psaty, JF Wilson, GDO Lowe, CJ O'Donnell, JCM Witteman, JW Jukema, IJ Deary, N Soranzo, W Koenig, C Hayward

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

51 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	Undefined/Unknown
Pages (from-to)	1864-+
Journal	Circulation
Volume	123
Issue number	17
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.110.009480
Publication status	Published - 2011

Research programs

EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01

Access to Document

10.1161/CIRCULATIONAHA.110.009480

http://hdl.handle.net/1765/25760

Cite this

Smith, NL., Huffman, JE., Strachan, DP., Huang, J., Dehghan, A., Trompet, S., Lopez, LM., Shin, SY., Baumert, J., Vitart, V., Bis, JC., Wild, SH., Rumley, A., Yang, Q., Uitterlinden, A., Stott, DJ., Davies, G., Carter, AM., Thorand, B., ... Hayward, C. (2011). Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults. Circulation, 123(17), 1864-+. https://doi.org/10.1161/CIRCULATIONAHA.110.009480

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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.)",

author = "NL Smith and JE Huffman and DP Strachan and J Huang and Abbas Dehghan and S Trompet and LM Lopez and SY Shin and J Baumert and V Vitart and JC Bis and SH Wild and A Rumley and Q Yang and Andr{\'e} Uitterlinden and DJ Stott and G Davies and AM Carter and B Thorand and O Polasek and B McKnight and H Campbell and AR Rudnicka and MH Chen and BM Buckley and SE Harris and A Peters and D Pulanic and T Lumley and {de Craen}, AJM and DC Liewald and C Gieger and S Campbell and I Ford and AJ Gow and M Luciano and DJ Porteous and XQ Guo and N Sattar and A Tenesa and M Cushman and Slagboom, {PE (Eline)} and PM Visscher and TD Spector and T Illig and I Rudan and EG Bovill and AF Wright and WL McArdle and G Tofler and Bert Hofman and RGJ Westendorp and JM Starr and PJ Grant and M Karakas and ND Hastie and BM Psaty and JF Wilson and GDO Lowe and CJ O'Donnell and JCM Witteman and JW Jukema and IJ Deary and N Soranzo and W Koenig and C Hayward",

year = "2011",

doi = "10.1161/CIRCULATIONAHA.110.009480",

language = "Undefined/Unknown",

volume = "123",

pages = "1864--+",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams & Wilkins",

number = "17",

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Smith, NL, Huffman, JE, Strachan, DP, Huang, J, Dehghan, A, Trompet, S, Lopez, LM, Shin, SY, Baumert, J, Vitart, V, Bis, JC, Wild, SH, Rumley, A, Yang, Q, Uitterlinden, A, Stott, DJ, Davies, G, Carter, AM, Thorand, B, Polasek, O, McKnight, B, Campbell, H, Rudnicka, AR, Chen, MH, 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, XQ, 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, B, 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-+. https://doi.org/10.1161/CIRCULATIONAHA.110.009480

TY - JOUR

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

AU - Smith, NL

AU - Huffman, JE

AU - Strachan, DP

AU - Huang, J

AU - Dehghan, Abbas

AU - Trompet, S

AU - Lopez, LM

AU - Shin, SY

AU - Baumert, J

AU - Vitart, V

AU - Bis, JC

AU - Wild, SH

AU - Rumley, A

AU - Yang, Q

AU - Uitterlinden, André

AU - Stott, DJ

AU - Davies, G

AU - Carter, AM

AU - Thorand, B

AU - Polasek, O

AU - McKnight, B

AU - Campbell, H

AU - Rudnicka, AR

AU - Chen, MH

AU - Buckley, BM

AU - Harris, SE

AU - Peters, A

AU - Pulanic, D

AU - Lumley, T

AU - de Craen, AJM

AU - Liewald, DC

AU - Gieger, C

AU - Campbell, S

AU - Ford, I

AU - Gow, AJ

AU - Luciano, M

AU - Porteous, DJ

AU - Guo, XQ

AU - Sattar, N

AU - Tenesa, A

AU - Cushman, M

AU - Slagboom, PE (Eline)

AU - Visscher, PM

AU - Spector, TD

AU - Illig, T

AU - Rudan, I

AU - Bovill, EG

AU - Wright, AF

AU - McArdle, WL

AU - Tofler, G

AU - Hofman, Bert

AU - Westendorp, RGJ

AU - Starr, JM

AU - Grant, PJ

AU - Karakas, M

AU - Hastie, ND

AU - Psaty, BM

AU - Wilson, JF

AU - Lowe, GDO

AU - O'Donnell, CJ

AU - Witteman, JCM

AU - Jukema, JW

AU - Deary, IJ

AU - Soranzo, N

AU - Koenig, W

AU - Hayward, C

PY - 2011

Y1 - 2011

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.)

U2 - 10.1161/CIRCULATIONAHA.110.009480

DO - 10.1161/CIRCULATIONAHA.110.009480

M3 - Article

C2 - 21502573

SN - 0009-7322

VL - 123

SP - 1864-+

JO - Circulation

JF - Circulation

IS - 17

ER -