Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction

Brain infarction is one of the common causes of death and also a major cause of severe disability. To identify a gene(s) susceptible to brain infarction, we performed a large-scale association study of Japanese patients with brain infarction, using 52608 gene-based single nucleotide polymorphism (SNP) markers. Comparison of allele frequencies between 1112 cases with brain infarction and age- and sex-matched control subjects of the same number found an SNP in the 5 0 -flanking region of angiotensin receptor like-1 (AGTRL1 )g ene (rs9943582, 2154G/A) to have a significant association with brain infarction [odds ratio 5 1.30, 95% confidence interval (CI) 5 1.14‐1.47, P 5 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. Luciferase assay and RT‐PCR analysis demonstrated that exogenously introduced Sp1 induced transcription of AGTRL1 and its ligand, apelin, as well, indicating direct regulation of apelin/APJ pathway by Sp1. Furthermore, a 14 year follow-up cohort study in a Japanese community in Hisayama town, Japan revealed that the homozygote of the susceptible G allele of this particular SNP had significantly higher risk of brain infarction (hazard ratio 5 2.00, 95% CI 5 1.22‐3.29, P 5 0.006). Our results indicate that the SNP in the AGTRL1 gene is associated with the susceptibility to brain infarction.