DNA sequence variation in CYP2A6 andnAChR alpha 7 genes and susceptibility for nicotine dependence in African Americans.

摘要

Twin studies suggest that nicotine dependence has a mean heritability of 53%. The prevalence of nicotine dependence appears to be higher in men than in women and it differs among ethnic groups in the United States. While little is known regarding genetic predisposition to nicotine dependence, the prevalence differences among ethnic groups suggest possible genetic effects which need to be explored, especially among African Americans. CYP2A6 enzyme is responsible for the majority of the metabolic conversion of nicotine to cotinine. Nicotine is a major ligand that binds to the nicotinic acetylcholinergic alpha7 receptors. These receptors within the VTA appear to be directly involved in nicotine-related reward and withdrawal responses. If these metabolizing and binding genes are involved in susceptibility to nicotine dependency, then variations in these may cause an increased risk of becoming dependent to nicotine due to altered enzymatic and receptor function, respectively.; In this study, the role of genetic variation on nicotine dependency risk was explored for genes, CYP2A6 and nAChRalpha7. DNA was isolated from whole blood from 454 subjects. All of the exons, the flanking intronic regions and 1,500 bases pairs of the promoter region of the CYP2A6 gene and 1,500 base pairs of the promoter region of the nAChRalpha7 gene was screened for DNA sequence variation using denaturing high performance liquid chromatography (dHPLC). Novel sequence variants for the CYP2A6 gene (N = 17) and the nAChRalpha7 (N = 3) were detected in DNA samples consisting of African American (n = 60), African Caribbean (n = 60), West African (n = 84), and European American (n = 60) individuals. Seven of these sequence variants were genotyped for a genetic association study on nicotine dependence using 190 African Americans. Single nucleotide polymorphisms (SNPs) were selected for genotyping if they potentially altered transcription binding sites or amino acids. Genotyping was performed using Pyrosequencing technology. Most of the SNPs genotyped for the CYP2A6 and nAChRalpha7 genes were found to be in linkage disequilibrium. CYP2A6 and nAChRalpha7 genotype and haplotype effects on nicotine dependency were determined by logistic regression.; No significant relationship was observed for any of the four CYP2A6 SNPs that were genotyped. However, the CYP2A6-30G/C promoter SNP revealed a slight trend of reducing the risk of nicotine dependence in the African American population (OR = 0.90; 95%CI .80--2.6; P = 0.06). (Abstract shortened by UMI.)