Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

Article, Other literature type English OPEN
Smith, Nicholas L ; Huffman, Jennifer E ; Strachan, David P ; Huang, Jie ; Dehghan, Abbas ; Trompet, Stella ; Lopez, Lorna M ; Shin, So-Youn ; Baumert, Jens ; Vitart, Veronique ; Bis, Joshua C ; Wild, Sarah H ; Rumley, Ann ; Yang, Qiong ; Uitterlinden, Andre G ; Stott, David J ; Davies, Gail ; Carter, Angela M ; Thorand, Barbara ; Polašek, Ozren ; McKnight, Barbara ; Campbell, Harry ; Rudnicka, Alicja R ; Chen, Ming-Huei ; Buckley, Brendan M ; Harris, Sarah E ; Peters, Annette ; Pulanic, Drazen ; Lumley, Thomas ; de Craen, Anton J M ... view all 66 authors (2011)
  • Publisher: LIPPINCOTT WILLIAMS & WILKINS
  • Journal: volume 123, issue 17, pages 1,864-1,872 (issn: 1524-4539, eissn: 1524-4539)
  • Related identifiers: doi: 10.1161/circulationaha.110.009480
  • Subject: coronary | Cardiology and Cardiovascular Medicine | meta-analysis | polymorphism | hemostasis | von-willebrand-factor | Physiology (medical) | Article | cardiovascular health | research | epidemiology | heart-disease | myocardial-infarction | /dk/atira/pure/subjectarea/asjc/2700/2705 | /dk/atira/pure/subjectarea/asjc/2700/2737 | thrombosis | tissue-plasminogen activator | thr312ala | venous thromboembolism | genome-wide association study | risk | genome-wide association | aging | fibrin fragment D

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.)