TY - JOUR
T1 - Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction
AU - Hata, Jun
AU - Matsuda, Koichi
AU - Ninomiya, Toshiharu
AU - Yonemoto, Koji
AU - Matsushita, Tomonaga
AU - Ohnishi, Yozo
AU - Saito, Susumu
AU - Kitazono, Takanari
AU - Ibayashi, Setsuro
AU - Iida, Mitsuo
AU - Kiyohara, Yutaka
AU - Nakamura, Yusuke
AU - Kubo, Michiaki
N1 - Funding Information:
We thank all the participated physicians and staff in the following hospitals for collecting subjects with brain infarction: Kyushu University Hospital, National Hospital Organization Kyushu Medical Center, National Hospital Organization Fukuoka Higashi Medical Center, Fukuoka Red Cross Hospital, Hakujuji Hospital, Imazu Red Cross Hospital and Seiai Rehabilitation Hospital. This study was supported in part by a grant from the Special Coordination Fund for Promoting Science to M.I. and a grant from the Technology and Innovative Development Project in Life Sciences (Ministry of Education, Culture, Sports, Science and Technology of Japan) to Y.K.
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/34247116957
UR - https://www.scopus.com/pages/publications/34247116957#tab=citedBy
U2 - 10.1093/hmg/ddm005
DO - 10.1093/hmg/ddm005
M3 - Article
C2 - 17309882
AN - SCOPUS:34247116957
SN - 0964-6906
VL - 16
SP - 630
EP - 639
JO - Human molecular genetics
JF - Human molecular genetics
IS - 6
ER -