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 journalArticlepeer-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 languageEnglish
Pages (from-to)1864-1872
Number of pages9
JournalCirculation
Volume123
Issue number17
DOIs
Publication statusPublished - Apr 2011

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

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