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 PolasekBarbara 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

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    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 pages17
    JournalCirculation
    Volume123
    Issue number17
    DOIs
    Publication statusPublished - 3 May 2011

    Keywords

    • RISK
    • MYOCARDIAL-INFARCTION
    • GENOME-WIDE ASSOCIATION
    • genome-wide association study
    • VON-WILLEBRAND-FACTOR
    • epidemiology
    • CORONARY HEART-DISEASE
    • meta-analysis
    • THR312ALA POLYMORPHISM
    • hemostasis
    • TISSUE-PLASMINOGEN ACTIVATOR
    • VENOUS THROMBOEMBOLISM
    • AGING RESEARCH
    • fibrin fragment D
    • thrombosis
    • CARDIOVASCULAR HEALTH

    Cite this

    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., ... Hayward, C. (2011). Genetic Predictors of Fibrin D-Dimer Levels in Healthy Adults. Circulation, 123(17), 1864-1872. https://doi.org/10.1161/CIRCULATIONAHA.110.009480