Abstract 4578: Common Genetic Variation In DDAH2 Is Associated With Intracerebral Hemorrhage in Chinese Population: A Multicenter Case-Control Study in China
Background Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), has been shown to be an independent predictor of coronary artery disease and stroke. The bulk of ADMA is degraded by an enzyme named dimethylarginine dimethylamin-ohydrolase (DDAH). DDAH2 was found in tissues that express endothelial isoforms of nitric oxide synthase. We hypothesized that genetic variation in DDAH2 might contribute to the susceptibility to stroke.
Methods The hypothesis was tested in 2 independent case-control studies. The stroke cases and controls were recruited from 7 centers in china. We use a haplotype-tagging SNP approach to identify tag single nucleotide polymorphisms (SNP) in DDAH2 region. The SNPs were genotyped in 1603 patients with stroke (719 cerebral thrombosis, 439 lacunar infarction, 445 intracerebral hemorrhage) and 1525 control subjects. The study was replicated in another independent case-control study including 381 patients with stroke and 843 control subjects.
Results Using the haplotype-tagging SNP approach, we identified a promoter variant -449G/C in DDAH2, which was the only tag-SNP in DDAH2 region and had been reported to be associated with changes in plasma ADMA level previously. SNP frequencies did not deviate from Hardy-Weinberg equilibrium (P> 0.05). Association analysis of the SNP using recessive, additive and dominant models were carried out. The SNP showed significant association with intracerebral hemorrhage assuming a dominant model. We found that the presence of the G allele of the -449 locus conferred 49% lower risk of intracerebral hemorrhage (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.38 to 0.68, P<0.001) compared to wild-type genotype. We observed no association between the DDAH2 variant with atherothrombotic stroke and lacunar infarction. The findings were confirmed in the second population.
Conclusions Our results suggest that the DDAH2 common variant may serve as novel genetic marker for the risk of intracerebral hemorrhage and strongly implicate that DDAH2/ADMA pathway act as a critical regulator of cerebral artery disorders.