Genetic predictors of fibrin D-Dimer levels in healthy adults

Smith, N. L. et al. (2011) Genetic predictors of fibrin D-Dimer levels in healthy adults. Circulation, 123(17), pp. 1864-1872. (doi: 10.1161/CIRCULATIONAHA.110.009480)

Full text not currently available from Enlighten.

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. <p/>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. <p/>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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rumley, Dr Ann and Lowe, Professor Gordon and Stott J, Professor David and Ford, Professor Ian
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., de Craen, A. J. M., 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. 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., and Hayward, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Circulation
ISSN:0009-7322
Published Online:18 April 2011

University Staff: Request a correction | Enlighten Editors: Update this record