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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.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.* ; de, Craen, A.J.* ; Liewald, D.C.* ; Gieger, C. ; Campbell, S.* ; Ford, I.* ; Gow, A.J.* ; Luciano, M.* ; Porteous, D.J.* ; Guo, X.* ; 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.* ; Starr, J.M.* ; Grant, P.J.* ; Karakas, M.* ; Hastie, N.D.* ; Psaty, B.M.* ; Wilson, J.F.* ; Lowe, G.D.* ; O'Donnell, C.J.* ; Witteman, J.C.* ; Jukema, J.W.* ; Deary, I.J.* ; Soranzo, N.* ; Koenig, W.* ; Hayward, C.

Genetic predictors of fibrin D-dimer levels in healthy adults.

Circulation 123, 1864-1872 (2011)

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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 ≈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=6.4×10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10(-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.

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