Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

被引：67

作者：

Smith, Nicholas L. ^{[1
,8
,9
]}

Huffman, Jennifer E. ^{[13
]}

Strachan, David P. ^{[5
]}

Huang, Jie ^{[20
]}

Dehghan, Abbas ^{[39
,46
]}

Trompet, Stella ^{[36
,37
]}

Lopez, Lorna M. ^{[30
,31
]}

Shin, So-Youn ^{[48
]}

Baumert, Jens ^{[28
]}

Vitart, Veronique ^{[13
]}

Bis, Joshua C. ^{[2
]}

Wild, Sarah H. ^{[14
]}

Rumley, Ann ^{[6
,40
]}

Yang, Qiong ^{[23
]}

Uitterlinden, Andre G. ^{[39
,46
,47
]}

Stott, David. J. ^{[40
]}

Davies, Gail ^{[31
]}

Carter, Angela M. ^{[51
]}

Thorand, Barbara ^{[28
]}

Polasek, Ozren ^{[15
,16
]}

McKnight, Barbara ^{[3
]}

Campbell, Harry ^{[14
]}

Rudnicka, Alicja R. ^{[5
]}

Chen, Ming-Huei ^{[24
]}

Buckley, Brendan M. ^{[43
]}

Harris, Sarah E. ^{[30
,33
]}

Peters, Annette ^{[28
]}

Pulanic, Drazen ^{[17
,18
]}

Lumley, Thomas ^{[3
]}

de Craen, Anton J. M. ^{[37
]}

Liewald, David C. ^{[30
,31
]}

Gieger, Christian ^{[26
]}

Campbell, Susan ^{[13
]}

Ford, Ian ^{[41
]}

Gow, Alan J. ^{[30
,31
]}

Luciano, Michelle ^{[30
,31
]}

Porteous, David J. ^{[30
,33
]}

Guo, Xiuqing ^{[12
]}

Sattar, Naveed

Tenesa, Albert ^{[13
,34
]}

Cushman, Mary ^{[10
,11
]}

Slagboom, P. Eline ^{[38
,39
]}

Visscher, Peter M. ^{[30
,35
]}

Spector, Tim D. ^{[49
,50
]}

Illig, Thomas ^{[27
]}

Rudan, Igor ^{[14
,15
,19
]}

Bovill, Edwin G. ^{[10
]}

Wright, Alan F. ^{[13
]}

McArdle, Wendy L. ^{[7
]}

Tofler, Geoffrey ^{[25
]}

机构：

[1] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA

[2] Univ Washington, Dept Med, Seattle, WA 98101 USA

[3] Univ Washington, Dept Biostat, Seattle, WA 98101 USA

[4] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA

[5] Univ London, Div Community Hlth Sci, London, England

[6] Univ Glasgow, Div Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[7] Univ Bristol, ALSPAC Lab, Bristol, Avon, England

[8] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA

[9] Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA

[10] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA

[11] Univ Vermont, Dept Med, Burlington, VT 05405 USA

[12] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[13] Western Gen Hosp, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[14] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[15] Gen Info Ltd, Zagreb, Croatia

[16] Univ Zagreb, Sch Med, Zagreb 41001, Croatia

[17] Clin Hosp Ctr Zagreb, Div Haematol, Dept Internal Med, Zagreb, Croatia

[18] Univ Osijek, Sch Med, Osijek, Croatia

[19] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia

[20] NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA

[21] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA

[22] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA

[23] Boston Univ, Dept Biostat, Boston, MA 02215 USA

[24] Boston Univ, Dept Neurol, Boston, MA 02215 USA

[25] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia

[26] German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[27] Unit Mol Epidemiol, Neuherberg, Germany

[28] Inst Epidemiol II, Neuherberg, Germany

[29] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, Ulm, Germany

[30] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[31] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland

[32] Univ Edinburgh, Geriatr Med Unit, Edinburgh, Midlothian, Scotland

[33] Univ Edinburgh, Med Genet Sect, Edinburgh, Midlothian, Scotland

[34] Univ Edinburgh, Roslin Inst, Royal Dick Sch Vet Studies, Roslin, Midlothian, Scotland

[35] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[36] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands

[37] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands

[38] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands

[39] Netherlands Consortium Healthy Ageing, Rotterdam, Netherlands

[40] Univ Glasgow, Div Cardiovasc & Med Sci, Glasgow, Lanark, Scotland

[41] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland

[42] Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland

[43] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland

[44] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands

[45] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands

[46] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[47] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands

[48] Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England

[49] Kings Coll London, Dept Twin Res, London WC2R 2LS, England

[50] Kings Coll London, Genet Epidemiol Unit, London WC2R 2LS, England

来源：

CIRCULATION | 2011年 / 123卷 / 17期

基金：

英国经济与社会研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金; 英国工程与自然科学研究理事会; 英国医学研究理事会;

关键词：

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;

D O I：

10.1161/CIRCULATIONAHA.110.009480

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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.)

引用

页码：1864 / +

页数：17

共 46 条

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