The impact of single nucleotide polymorphism (SNP) in the angiotensin receptor like-1 (AGTRL1) gene on the development of ischemic stroke

Abstract

Background and purpose: Genetic factors associated with ischemic stroke are still not well understood. To identify a gene susceptible to ischemic stroke, we performed a genome-wide association study of ischemic stroke using 52,608 single nucleotide polymorphism (SNP) markers.
Methods and results: We performed two-step screening analysis using 1,112 cases with ischemic stroke and age- and sex-matched control subjects of the same number. After a linkage disequilibrium analysis in a candidate locus, we found an SNP in the 5'-flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, -154 G/A) to have a significant association with ischemic stroke(odds ratio, 1.30; 95% confidence interval (CI), 1.14-1.47; p=0.000066). We also found the binding of Sp1 transcription factor to the region including the susceptible G allele, but not the non-susceptible A allele. Real-time PCR analysis and luciferase assay demonstrated that exogenously introduced Sp1 induced transcription of AGTRL1. Furthermore, a 14 year follow-up cohort study in a Japanese community in Hisayama Town revealed that the GG genotype of this particular SNP had a significantly higher risk of ischemic stroke (hazard ratio, 2.00; 95%CI, 1.22-3.29; p=0.006).
Conclusion: Our results indicate that the SNP in the AGTRL1 gene is significantly associated with the susceptibility to ischemic stroke.