title: Functional polymorphisms in the sigma1 receptor gene associated with alcoholism.
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.
authors.affiliation: Institute of Clinical Research, National Alcoholism Center Kurihama Hospital, Kanagawa, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Miyatake
authors.forename: Aizo
authors.initials: A
authors.lastname: Furukawa
authors.forename: Sachio
authors.initials: S
authors.lastname: Matsushita
authors.forename: Susumu
authors.initials: S
authors.lastname: Higuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suwaki
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000208:ethnology / Q000235:genetics* / Q000534:rehabilitation; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D016022:Case-Control Studies; D039721:Diagnostic and Statistical Manual of Mental Disorders; D015870:Gene Expression / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006760:Hospitalization; D006801:Humans; D007564:Japan; D008297:Male; D010554:Personality Disorders / Q000175:diagnosis / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D017480:Receptors, sigma / Q000235:genetics* / Q000502:physiology; D012720:Severity of Illness Index; D014158:Transcription, Genetic; D000097605:Sigma-1 Receptor
chemical_list: D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C096127:ALDH2 protein, human