Common genetic variation in DDAH2 is associated with intracerebral haemorrhage in a Chinese population: a multi-centre case-control study in China

ADMA (asymmetric ω-N^G,N^G-dimethylarginine), an endogenous inhibitor of NOS (NO synthase), has been shown to be an independent predictor of cerebrovascular disorders. DDAH2 (dimethylarginine dimethylaminohydrolase 2) promotes the metabolism of ADMA and plays a key role in the regulation of the acute inflammatory response. We hypothesized that genetic variation in DDAH2 might alter the susceptibility to ICH (intracerebral haemorrhage). The hypothesis was tested in two independent case-control studies. We used a haplotype-tagging SNP (single nucleotide polymorphism) approach to identify tag SNPs in DDAH2. The SNPs were genotyped in 1603 stroke patients and 1525 control subjects. The study was replicated in another independent case-control study including 322 stroke patients and 891 control subjects. A promoter variant −449C/G (rs805305) in DDAH2 was identified and found to be in complete linkage disequilibrium with the only tag SNP (rs707916) in the region containing DDAH2. Genotype analyses were conducted for both dominant and additive models. The C allele of the −449 locus resulted in a significantly reduced risk of ICH {dominant model: OR (odds ratio), 0.51 [95% CI (confidence interval), 0.38–0.68], P=6.60×10⁻⁶; additive model: OR, 0.64 (95% CI, 0.52–0.80), P=5.21×10⁻⁵} than the wild-type genotype. No association was observed between the DDAH2 variant and atherothrombotic stroke. The findings were replicated in the second independent population. In conclusion, our results suggest that the DDAH2 common variant may play a protective role in the development of ICH, implicating that the DDAH2/ADMA pathway may act as a critical regulator of cerebral small-vessel disorders.