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    Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults

    Smith, Nicholas L. and Huffman, Jennifer E. and Strachan, David P. and Huang, Jie and Dehghan, Abbas and Trompet, Stella and Lopez, Lorna M. and Shin, So-Youn and Baumert, Jens and Vitart, Veronique and Bis, Joshua C. and Wild, Sarah H. and Rumley, Ann and Yang, Qiong and Uitterlinden, Andre G. and Stott, David. J. and Davies, Gail and Carter, Angela M. and Thorand, Barbara and Polašek, Ozren and McKnight, Barbara and Campbell, Harry and Rudnicka, Alicja R. and Chen, Ming-Huei and Buckley, Brendan M. and Harris, Sarah E. and Peters, Annette and Pulanic, Drazen and Lumley, Thomas and de Craen, Anton J.M. and Liewald, David C. and Gieger, Christian and Campbell, Susan and Ford, Ian and Gow, Alan J. and Luciano, Michelle and Porteous, David J. and Guo, Xiuqing and Sattar, Naveed and Tenesa, Albert and Cushman, Mary and Slagboom, P. Eline and Visscher, Peter M. and Spector, Tim D. and Illig, Thomas and Rudan, Igor and Bovill, Edwin G. and Wright, Alan F. and McArdle, Wendy L. and Tofler, Geoffrey and Hofman, Albert and Westendorp, Rudi G.J. and Starr, John M. and Grant, Peter J. and Karakas, Mahir and Hastie, Nicholas D. and Psaty, Bruce M. and Wilson, James F. and Lowe, Gordon D.O. and O'Donnell, Christopher J. and Witteman, Jacqueline C.M. and Jukema, J. Wouter and Deary, Ian J. and Soranzo, Nicole and Koenig, Wolfgang and Hayward, Caroline (2011) Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults. Circulation, 123 (17). pp. 1864-1872. ISSN 0009-7322

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    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. 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. Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

    Item Type: Article
    Keywords: genome-wide variation; D-dimer; epidemiology; meta-analysis; thrombosis; hemostasis;
    Academic Unit: Faculty of Science and Engineering > Biology
    Faculty of Science and Engineering > Research Institutes > Human Health Institute
    Item ID: 17399
    Identification Number:
    Depositing User: Lorna Lopez
    Date Deposited: 10 Jul 2023 15:46
    Journal or Publication Title: Circulation
    Publisher: Lippincott, Williams & Wilkins
    Refereed: Yes
    Use Licence: This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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