Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

Smith, N.L.; Huffman, J.E.; Strachan, D.P.; Huang, J.; Dehghan, A.; Trompet, S.; ... ; Hayward, C. (2011)

Article / Letter to editor

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.)

• 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

• All authors: 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.; Polasek, O.; McKnight, B.; Campbell, H.; Rudnicka, A.R.; Chen, M.H.; Buckley, B.M.; Harris, S.E.; Peters, A.; Pulanic, D.; Lumley, T.; Craen, A.J.M. de; Liewald, D.C.; Gieger, C.; Campbell, S.; Ford, I.; Gow, A.J.; Luciano, M.; Porteous, D.J.; Guo, X.Q.; Sattar, N.; Tenesa, A.; Cushman, M.; Slagboom, P.E.; Visscher, P.M.; Spector, T.D.; Illig, T.; Rudan, I.; Bovill, E.G.; Wright, A.F.; McArdle, W.L.; Tofler, G.; Hofman, A.; Westendorp, R.G.J.; Starr, J.M.; Grant, P.J.; Karakas, M.; Hastie, N.D.; Psaty, B.M.; Wilson, J.F.; Lowe, G.D.O.; O'Donnell, C.J.; Witteman, J.C.M.; Jukema, J.W.; Deary, I.J.; Soranzo, N.; Koenig, W.; Hayward, C.
• Date: 2011-05-03
• Journal: Circulation
• Volume: 123
• Issue: 17
• Pages: 1864
• DOI: doi:10.1161/CIRCULATIONAHA.110.009480