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

Hum Mol Genet. 2007 Mar 15;16(6):630-9. doi: 10.1093/hmg/ddm005. Epub 2007 Feb 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Flanking Region
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Apelin
  • Apelin Receptors
  • Asian Continental Ancestry Group
  • Brain Infarction / genetics*
  • Case-Control Studies
  • Cell Line
  • Cell Line, Tumor
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Gene Expression
  • Genetic Predisposition to Disease*
  • Homozygote
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Japan
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • RNA, Messenger
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism*
  • Risk Factors
  • Sp1 Transcription Factor / metabolism


  • APLN protein, human
  • APLNR protein, human
  • Apelin
  • Apelin Receptors
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Sp1 Transcription Factor