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Genetic predictors of fibrin D-dimer levels in healthy adults.
Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
| Title | Genetic predictors of fibrin D-dimer levels in healthy adults. |
| Publication Type | Journal Article |
| Year of Publication | 2011 |
| Authors | Smith, NL, Huffman, JE, Strachan, DP, Huang, J, Dehghan, A, Trompet, S, Lopez, LM, Shin, S-Y, Baumert, J, Vitart, V, Bis, JC, Wild, SH, Rumley, A, Yang, Q, Uitterlinden, AG, Stott, DJ, Davies, G, Carter, AM, Thorand, B, Polasek, O, McKnight, B, Campbell, H, Rudnicka, AR, Chen, M-H, Buckley, BM, Harris, SE, Peters, A, Pulanic, D, Lumley, T, de Craen, AJM, Liewald, DC, Gieger, C, Campbell, S, Ford, I, Gow, AJ, Luciano, M, Porteous, DJ, Guo, X, Sattar, N, Tenesa, A, Cushman, M, P Slagboom, E, Visscher, PM, Spector, TD, Illig, T, Rudan, I, Bovill, EG, Wright, AF, McArdle, WL, Tofler, G, Hofman, A, Westendorp, RGJ, Starr, JM, Grant, PJ, Karakas, M, Hastie, ND, Psaty, BM, Wilson, JF, Lowe, GDO, O'Donnell, CJ, Witteman, JCM, J Jukema, W, Deary, IJ, Soranzo, N, Koenig, W, Hayward, C |
| Journal | Circulation |
| Volume | 123 |
| Issue | 17 |
| Pagination | 1864-72 |
| Date Published | 2011 May 03 |
| ISSN | 1524-4539 |
| Keywords | Adult, Aged, Blood Coagulation, European Continental Ancestry Group, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Testing, Genome-Wide Association Study, Humans, Male, Middle Aged, Reference Values, Thromboplastin |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS AND RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.</p> |
| DOI | 10.1161/CIRCULATIONAHA.110.009480 |
| Alternate Journal | Circulation |
| PubMed ID | 21502573 |
| PubMed Central ID | PMC3095913 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States HL073410 / HL / NHLBI NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom R01 HL095080 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States U.1275.00.001(61128) / / Medical Research Council / United Kingdom MC_U127561128 / / Medical Research Council / United Kingdom N01 HC015103 / HC / NHLBI NIH HHS / United States 079895 / / Wellcome Trust / United Kingdom CZB/4/276 / / Chief Scientist Office / United Kingdom 091746/Z/ / / Wellcome Trust / United Kingdom R01 HL087652 / HL / NHLBI NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States SAG09977 / / Biotechnology and Biological Sciences Research Council / United Kingdom U01 DK062418 / DK / NIDDK NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States R01 HL 087652 / HL / NHLBI NIH HHS / United States N01-HC-55222 / HC / NHLBI NIH HHS / United States 068545 / / Wellcome Trust / United Kingdom K24 DK080140 / DK / NIDDK NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States 079996 / / Wellcome Trust / United Kingdom MC_PC_U127561128 / / Medical Research Council / United Kingdom 091746 / / Wellcome Trust / United Kingdom M01 RR000425 / RR / NCRR NIH HHS / United States HL095080 / HL / NHLBI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States G0700704 / / Medical Research Council / United Kingdom N01-HC-85079 / HC / NHLBI NIH HHS / United States 068545/Z/02 / / Wellcome Trust / United Kingdom BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom MC_QA137934 / / Medical Research Council / United Kingdom N01HC85079 / HL / NHLBI NIH HHS / United States R01 HL073410 / HL / NHLBI NIH HHS / United States 076113/B/04/Z / / Wellcome Trust / United Kingdom N01 HC045133 / HC / NHLBI NIH HHS / United States G0000934 / / Medical Research Council / United Kingdom N01 HC035129 / HC / NHLBI NIH HHS / United States |