A genetic association study of D-dimer levels with 50 K SNPs from a candidate gene chip in four ethnic groups
ABSTRACT 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 x 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.
SourceAvailable from: ncbi.nlm.nih.gov[Show abstract] [Hide abstract]
ABSTRACT: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study. 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE. In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors. These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.Thrombosis Research 02/2007; 121(1):1-7. DOI:10.1016/j.thromres.2007.02.008 · 2.43 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: There is growing evidence that fibrin D-dimer is associated with coronary and peripheral atherosclerosis. Using data from the Edinburgh Artery Study, we examined the distribution of fibrin D-dimer in 1592 men and women 55 to 74 years old and assessed its relationship with a range of cardiovascular risk factors. Fibrin D-dimer levels were higher in women than in men (P < or = .05) and increased with age (P < or = .001). Current cigarette smokers had higher levels than ex-smokers, who, in turn, had higher levels than those who had never smoked. On multiple regression analyses with age and plasma fibrinogen as covariates, only lifetime smoking in men and systolic blood pressure in women were independent predictors of fibrin D-dimer levels. Since fibrin D-dimer does not appear to be independently related to many of the common cardiovascular risk factors, it may be a useful index of the thrombotic contribution to arterial disease.Arteriosclerosis Thrombosis and Vascular Biology 09/1995; 15(8):1094-7. DOI:10.1161/01.ATV.15.8.1094 · 5.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.Journal of Thrombosis and Haemostasis 09/2003; 1(8):1799-804. DOI:10.1046/j.1538-7836.2003.00255.x · 5.55 Impact Factor