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

Author： Hata Jun Matsuda Koichi Ninomiya Toshiharu Yonemoto Koji Matsushita Tomonaga Ohnishi Yozo Saito Susumu Kitazono Takanari Ibayashi Setsuro Iida Mitsuo Kiyohara Yutaka Nakamura Yusuke Kubo Michiaki

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.16, Iss.6, 2007-03, pp. : 630-639

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Abstract

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′-flanking region of angiotensin receptor like-1 (AGTRL1) gene (rs9943582, − 154G/A) to have a significant association with brain infarction [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. 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 = 2.00, 95% CI = 1.22–3.29, P = 0.006). Our results indicate that the SNP in the AGTRL1 gene is associated with the susceptibility to brain infarction.