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 Polašek; 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 PolašekBarbara 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

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

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	9
Journal	Circulation
Volume	123
Issue number	17
DOIs	https://doi.org/10.1161/circulationaha.110.009480
Publication status	Published - Apr 2011

Keywords / Materials (for Non-textual outputs)

epidemiology
fibrin fragment D
genome-wide association study
hemostasis
meta-analysis
thrombosis
genome-wide association
tissue-plasminogen activator
coronary
heart-disease
von-willebrand-factor
venous thromboembolism
thr312ala
polymorphism
cardiovascular health
myocardial-infarction
aging
research
risk

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10.1161/circulationaha.110.009480

Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults
EuropePMC funders group author manuscript
Accepted author manuscript, 355 KB

http://circ.ahajournals.org/content/123/17/1864

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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{f0d3474672ab47259407868ae08e20ac,

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 = "epidemiology, fibrin fragment D, genome-wide association study, hemostasis, meta-analysis, thrombosis, genome-wide association, tissue-plasminogen activator, coronary, heart-disease, von-willebrand-factor, venous thromboembolism, thr312ala, polymorphism, cardiovascular health, myocardial-infarction, aging, research, risk",

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 Pola{\v s}ek 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 = apr,

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, Polašek, 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 - Polašek, 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 - 2011/4

Y1 - 2011/4

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 - epidemiology

KW - fibrin fragment D

KW - genome-wide association study

KW - hemostasis

KW - meta-analysis

KW - thrombosis

KW - genome-wide association

KW - tissue-plasminogen activator

KW - coronary

KW - heart-disease

KW - von-willebrand-factor

KW - venous thromboembolism

KW - thr312ala

KW - polymorphism

KW - cardiovascular health

KW - myocardial-infarction

KW - aging

KW - research

KW - risk

UR - http://www.scopus.com/inward/record.url?scp=79955635525&partnerID=8YFLogxK

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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Disconnected Mind [Phase 2]

MRC Centre for Cognitive Ageing and Cognitive Epidemiology

A genome wide association study of non pathological cognitive ageing

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Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

Disconnected Mind [Phase 2]

MRC Centre for Cognitive Ageing and Cognitive Epidemiology

A genome wide association study of non pathological cognitive ageing

Cite this