title: Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction.
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.
authors.affiliation: Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hata
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Koji
authors.initials: K
authors.lastname: Yonemoto
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Matsushita
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnishi
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
authors.forename: Setsuro
authors.initials: S
authors.lastname: Ibayashi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iida
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kiyohara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
mesh_terms: D024506:5' Flanking Region; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000073861:Apelin; D000075244:Apelin Receptors; D044466:Asian People; D020520:Brain Infarction / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007564:Japan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D012307:Risk Factors; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D016329:Sp1 Transcription Factor