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Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.

ABSTRACT: Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these approximately 7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P=6.9 x 10(-5)). In a third set of European populations (n= approximately 7500) which had been genotyped for approximately 6000 SNPs in approximately 2000 genes, an allele in the same haplotype was associated with CPD (nominal P=2.6 x 10(-6)). These results (in three independent populations of European origin, totaling approximately 15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.

SUBMITTER: Berrettini W

PROVIDER: S-EPMC2507863 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.

Berrettini W W Yuan X X Tozzi F F Song K K Francks C C Chilcoat H H Waterworth D D Muglia P P Mooser V V

Molecular psychiatry 20080129 4

Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these approximately 7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD ...[more]

PMID: 18227835

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Project description:BACKGROUND:The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. METHODS:This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. RESULTS:Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P?=?0.03, n?=?389; P?=?0.01, n?=?391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR?=?1.63; 95% CI?=?1.04 to 2.54; P?=?0.03 and OR?=?1.59, 95% CI?=?1.02 to 2.48; P?=?0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CONCLUSION:CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.

Dataset Information

Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.

Publications

Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.

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