Functional polymorphisms in the sigma1 receptor gene associated with alcoholism

Biol Psychiatry. 2004 Jan 1;55(1):85-90. doi: 10.1016/j.biopsych.2003.07.008.

Abstract

Background: Sigma1 receptors are involved in the pathogenesis of drug abuse. Two polymorphisms (GC-241-240TT and Gln2Pro) in the sigma1 receptor gene (SIGMAR1) have been identified. To investigate the role of SIGMAR1 in conveying susceptibility to alcoholism, we performed a functional analysis of polymorphisms in the SIGMAR1 and a case-control study.

Methods: We initially screened for polymorphisms in the 5'-upstream region. The effects of the polymorphisms on transcriptional activity were determined using a gene reporter assay. The distribution of SIGMAR1 polymorphisms was analyzed in 307 alcoholic and 302 control subjects.

Results: A novel T-485A polymorphism was identified. The transcriptional activity of the A-485 allele and the TT-241-240 allele was significantly reduced compared with that of the T-485 allele and the GC-241-240 allele. The frequencies of the A-485 allele (chi2=5.575, df=1, p=.0205) and the TT-241-240/Pro2 haplotype (chi2=21.464, df=1, p<.0001) were significantly higher in control subjects compared with alcoholic subjects. The T-485A and the GC-241-240TT may be functional polymorphisms, and the A-485 allele and TT-241-240/Pro2 haplotype are possible protective factors for the development of alcoholism.

MeSH terms

  • Adult
  • Alcoholism / ethnology
  • Alcoholism / genetics*
  • Alcoholism / rehabilitation
  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase, Mitochondrial
  • Case-Control Studies
  • Diagnostic and Statistical Manual of Mental Disorders
  • Gene Expression / genetics*
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes / genetics
  • Hospitalization
  • Humans
  • Japan
  • Male
  • Personality Disorders / diagnosis
  • Personality Disorders / epidemiology
  • Polymorphism, Genetic / genetics*
  • Receptors, sigma / genetics*
  • Receptors, sigma / physiology
  • Severity of Illness Index
  • Sigma-1 Receptor
  • Transcription, Genetic

Substances

  • Receptors, sigma
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial