A genetic association study of D-dimer levels with 50 K SNPs from a candidate gene chip in four ethnic groups

Introduction D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations. Materials and Methods We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis. Results Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0 × 10^{- 6}. The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer. Conclusions Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.