Functional polymorphisms in the sigma1 receptor gene associated with alcoholism
Received 24 February 2003; received in revised form 17 July 2003; accepted 24 July 2003.
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 (χ2 = 5.575, df = 1, p = .0205) and the TT-241-240/Pro2 haplotype (χ2 = 21.464, df = 1, p < .0001) were significantly higher in control subjects compared with alcoholic subjects.
Conclusions
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.
aInstitute of Clinical Research, National Alcoholism Center Kurihama Hospital (RM, SM, SH), Kanagawa, Japan
bDepartment of Neuropsychiatry, Faculty of Medicine, Kagawa Medical University (RM, HS), Kagawa, Japan
cDepartment of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital (AF), Tokyo, Japan
Address reprint requests to Dr. R. Miyatake, Institute of Clinical Research, National Alcoholism Center Kurihama Hospital, 5-3-1 Nobi, Yokosuka, Kanagawa 239-0841, Japan.
ABSTRACT