Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population

PLoS One. 2013;8(3):e58538. doi: 10.1371/journal.pone.0058538. Epub 2013 Mar 6.

Abstract

Angiotensin II type 1 receptor (AGTR1) has been reported to play a fibrogenic role in non-alcoholic fatty liver disease (NAFLD). In this study, five variants of the AGTR1 gene (rs3772622, rs3772627, rs3772630, rs3772633, and rs2276736) were examined for their association with susceptibility to NAFLD. Subjects made up of 144 biopsy-proven NAFLD patients and 198 controls were genotyped using TaqMan assays. The liver biopsy specimens were histologically graded and scored according to the method of Brunt. Single locus analysis in pooled subjects revealed no association between each of the five variants with susceptibility to NAFLD. In the Indian ethnic group, the rs2276736, rs3772630 and rs3772627 appear to be protective against NAFLD (p = 0.010, p = 0.016 and p = 0.026, respectively). Haplotype ACGCA is shown to be protective against NAFLD for the Indian ethnic subgroup (p = 0.03). Gene-gene interaction between the AGTR1 gene and the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which we previously reported as associated with NAFLD in this sample, showed a strong interaction between AGTR1 (rs3772627), AGTRI (rs3772630) and PNPLA3 (rs738409) polymorphisms on NAFLD susceptibility (p = 0.007). Further analysis of the NAFLD patients revealed that the G allele of the AGTR1 rs3772622 is associated with increased fibrosis score (p = 0.003). This is the first study that replicates an association between AGTR1 polymorphism and NAFLD, with further details in histological features of NAFLD. There is lack of evidence to suggest an association between any of the five variants of the AGTR1 gene and NAFLD in the Malays and Chinese. In the Indians, the rs2276736, rs3772630 and rs3772627 appear to protect against NAFLD. We report novel findings of an association between the G allele of the rs3772622 with occurrence of fibrosis and of the gene-gene interaction between AGTR1gene and the much-studied PNPLA3 gene.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian People
  • Epistasis, Genetic / genetics
  • Fatty Liver / ethnology
  • Fatty Liver / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Linkage Disequilibrium
  • Lipase / genetics
  • Logistic Models
  • Membrane Proteins / genetics
  • Non-alcoholic Fatty Liver Disease
  • Polymorphism, Single Nucleotide / genetics*
  • ROC Curve
  • Receptor, Angiotensin, Type 1 / genetics*
  • Statistics, Nonparametric
  • White People

Substances

  • AGTR1 protein, human
  • Membrane Proteins
  • Receptor, Angiotensin, Type 1
  • Lipase
  • adiponutrin, human

Grants and funding

This study was supported by University Malaya Research Grant RG069/09HTM and RG364/11HTM, and by the High Impact Research Ministry of Higher Education (HIRMOHE) Grant E000025-20001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.