Abstract
Introduction: D-dimer, a marker of blood coagulation and fibrinolysis, is a widely-used biomarker of venous thromboembolism. While the coagulation factors V, III, II and fibrinogen alpha chain genes contain known genetic determinants of D-dimer, other determinants are not well characterized, especially in populations other than European Americans (EAs); no data have been reported for Asian American populations. Hypothesis: Large-scale candidate gene association analysis will identify D-dimer related gene variants in EA, African-American (AA), Chinese, and Hispanic populations. Methods: Four cohorts, comprised of 6,848 EA, 2,192 AAs, 670 Chinese, and 1,286 Hispanics from Cleveland Family Study, Cardiovascular Health Study, Framingham Heart Study, and Multi-Ethnic Study of Atherosclerosis in the Candidate Gene Association Resource (CARe) consortium, were included. The inverse normal transformed residual of D-dimer was used in genetic analysis. About 50,000 SNPs located in 2,100 inflammation and atherosclerosis-related genes were genotyped using the custom ITMAT-Broad-CARe (IBC) chip and analyzed by linear regression adjusted for age, sex, study site, and principal components to account for potential population stratification in each cohort and race group. Significance was set at p<2x10-6 after accounting for multiple testing. Results: Twelve SNPs in the coagulation factor V gene and 3 SNPs in the fibrinogen alpha chain genes exceeded the significant p-value threshold in EA. The top SNPs in these two regions were rs6025 (p-value=7.41x10-16) and rs13109457 (p-value=7.52x10-7), respectively. The signals for the remaining significant SNPs in these two regions were no longer statistically significant after adjusting for the known functional SNPs in each region (rs6025 and rs6050, respectively). The top signal at the coagulation factor V gene was replicated in Hispanics but not other race groups. Neither AA nor the other race groups replicated the signals for fibrinogen alpha chain gene. No additional variants in AA, Chinese, or Hispanics showed significant associations with D-dimer, but several SNPs in neuregulin 1 and Bruton agammaglobulinemia tyrosine kinase for AA and vanin 1 for Chinese were suggestively associated with D-dimer levels (p-value<5x10-5). Conclusion: Our study replicated previously reported associations of D-dimer with coagulation factor V and fibrinogen alpha chain variants in EAs and identified coagulation factor V variation in Hispanics. Additional studies are required to confirm the suggestive findings in AAs, Chinese, and Hispanic populations.
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