A Novel Functional Polymorphism in the NINJ2 Promoter Predicts Risk of Large Artery Atherosclerotic Stroke

A recent genome-wide association study (GWAS) identified two common polymorphisms (rs12425791 and rs11833579) on chromosome 12p13 that confer risk to stroke, particularly for large artery atherosclerotic (LAA) stroke. However, these two polymorphisms are located ∼11 kb upstream of the NINJ2 gene and their effects on NINJ2 expression have not been well characterized. Through linkage disequilibrium and fine-mapping analysis, we identified a novel functional polymorphism in the NINJ2 promoter (rs3809263 G > A) and examined its association with risk of LAA stroke in Chinese population. Rs3809263 was genotyped using the improved multiple ligase detection reaction in 414 patients with LAA stroke and 423 healthy controls. A significant decreased risk of LAA stroke was found for the rs3809263 GA (adjusted odd ratio [OR] = 0.63, 95 % confidence interval [CI] = 0.46–0.88) and AA (OR = 0.54, 95 % CI = 0.35–0.84) genotypes. Moreover, genotype-phenotype correlation analysis indicated that the AA genotype carriers had significantly increased NINJ2 mRNA expression levels in the Chinese population, suggesting that the rs3809263 G > A polymorphism is a functional SNP and a biomarker for risk of LAA stroke. Further validation of the functionality of the NINJ2 rs3809263 G > A polymorphism and its association with risk of LAA stroke in other ethnic populations is warranted.