Genetic Susceptibility Of Stroke And CHD In Han Chinese Population

Background and Purpose—The first genome-wide association (GWA) study of ischemic stroke on Caucasians has identified multiple susceptibility loci. Here we confirmed this study by examining associations with ischemic stroke in Chinese Han population.Methods—Twenty five common variants were genotyped in a relatively large sample size including 1123 subjects with ischemic stroke cases (thrombosis stroke=716, lacunar infarction=407) and 557 normal controls. The association analyses were performed at both SNP and haplotype levels. FDR q value method was applied for multiple testing corrections.Results—Rsl1052413, a intergenic SNP, was most significantly associated with ischemic stroke independent of traditional cardiovascular risk factors in additive (OR=1.51,95% CI: 1.19-1.92, P=7.4×10-4, q=0.018) and dominant model (OR=1.59,95% CI:1.20-2.08, P= 9.2×10-4, q=0.023). In addition, both ZNF650 rs10204475 and intergenic SNP rs10486776 were associated with ischemic stroke as well independent of traditional cardiovascular risk factors in dominant models (OR=1.47,95% CI:1.12-1.96, P=0.005, q=0.040; OR=1.53, 95% CI:1.15-2.02, P=0.003, q-0.036; respectively). No significant results were found in stroke subtype analysis after multiple corrections.Conclusion—Our study confirmed previously reported associations between ischemic stroke and rs11052413, rs10486776 and ZNF 650 rs10204475 in Chinese Han population. The mechanism whereby the genetic variants exert their effects on ischemic stroke remains to be further elucidated. Background and Purpose—Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction. In the present study, we tested whether a novel genetic variant in dimethylarginine dimethylaminohydrolasel (DDAH1), an important ADMA hydrolyzing gene, was associated with stroke and coronary heart disease (CHD) susceptibility in the Chinese Han population.Methods and Results—By resequencing, we identified a novel 4-nucleotide deletion/insertion variant in the DDAHl promoter. The insertion allele disrupted binding of metal-regulatory transcription factor 1 (MTF1), which resulted insignificant reduction of in vitro DDAH1 transcriptional activity and in vivo DDAH1 mRNA level, and in turn, increased plasma ADMA level and the ratio of ADMA to L-arginine. We initially genotyped the polymorphism in 1388 stroke patients and 1027 controls as well as 576 CHD patients and 557 controls and then replicated our study in additional independent case-control cohorts comprising 961 stroke patients and 822 controls and 482 CHD patients and 1072 controls. We identified that the-396 4N ins allele was significantly associated with increased risk of thrombosis stroke and CHD after adjusting for environmental factors in both samples for both diseases (thrombosis stroke discovery set:odds ratio [OR]=1.35, P=0.032; replication set:OR=1.51, P=0.006; CHD discovery set:OR=1.45,P=0.035; replication set:OR=1.47, P=0.003).Conclusion—Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD.