Convergence of genetic findings for nicotine dependence and smoking related diseases with chromosome 15q24-25.
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ABSTRACT:
SUBMITTER: Bierut LJ
PROVIDER: S-EPMC2993565 | biostudies-literature | 2010 Jan
REPOSITORIES: biostudies-literature
Publications
Convergence of genetic findings for nicotine dependence and smoking related diseases with chromosome 15q24-25.
Trends in pharmacological sciences 20091105 1
Due to the adverse health consequences related to smoking, it is important to understand factors that contribute to nicotine dependence. The most replicated genetic finding for nicotine dependence points to variants on chromosome 15, which includes the alpha5-alpha3-beta4 nicotinic receptor gene cluster. A compelling functional variant is a polymorphism, rs16969968, which alters an amino acid in the alpha5 nicotinic receptor subunit. Several prominent studies report that the replicated nicotine ...[more]
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Project description:Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies, with no consensus as to the relative impact of the variants on the propensity to smoke vs a direct carcinogenic effect. To further explore our hypothesis that these variants are indeed associated with both cancer causation and nicotine dependence, we performed a more detailed analysis of the association of these putative risk genotypes with smoking phenotype, as well as in lifetime never smokers, and in other smoking-related cancers. We demonstrate a statistically significant association of the variants with both nicotine dependence, as well as lung cancer phenotypes, including earlier age at lung cancer onset. The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects, nor in other smoking-related cancers (bladder and renal). Thus, we conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk.
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Project description:IntroductionGenetic variation in Cytochrome P450 2A6 (CYP2A6), the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations.Aims and methodsAdult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n = 567) or slow (n = 432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. Fagerström test for nicotine dependence scores were measured at baseline and biochemically verified smoking cessation was assessed at end of treatment.ResultsDependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n = 591 European, n = 408 African ancestry) or sex (n = 444 women, n = 555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95 to 1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e. interaction) effect ORs ranged from 0.88 to 1.61 (p = .397-.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high versus low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high versus low dependence had lower quit rates in all three treatment arms.ConclusionsAlthough nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers.ImplicationsVariation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.
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Project description:A common variant on chromosomal region 15q24-25.1, marked by rs1051730, was found to be associated with lung cancer risk. Here, we attempted to confirm the second variant on 15q24-25.1 in several large sporadic lung cancer populations and determined what percentage of additional risk for lung cancer is due to the genetic effect of the second variant. SNPs rs1051730 and rs481134 were genotyped in 2,818 lung cancer cases and 2,766 controls from four populations. Joint analysis of these two variants (rs1051730 and rs481134) on 15q24-25.1 identified three major haplotypes (G_T, A_C, and G_C) and provided stronger evidence for association of 15q24-25.1 with lung cancer (P = 9.72 x 10(-9)). These two variants represent three levels of risk associated with lung cancer. The most common haplotype G_T is neutral; the haplotype A_C is associated with increased risk for lung cancer with 5.0% higher frequency in cases than in controls [P = 1.68 x 10(-7); odds ratio (OR), 1.24; 95% confidence interval (95% CI), 1.14-1.35]; whereas the haplotype G_C is associated with reduced risk for lung cancer with 4.4% lower frequency in cases than in controls (P = 7.39 x 10(-7); OR, 0.80; 95% CI, 0.73-0.87). We further showed that these two genetic variants on 15q24-25.1 independently influence lung cancer risk (rs1051730: P = 4.42 x 10(-11); OR, 1.60; 95% CI, 1.46-1.74; rs481134: P = 7.01 x 10(-4); OR, 0.81; 95% CI, 0.72-0.92). The second variant on 15q24-25.1, marked by rs481134, explains an additional 13.2% of population attributable risk for lung cancer.
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Project description:BackgroundPeer smoking provides a socially reinforcing context of friends' encouragement and approval that contributes to smoking behavior. Twin studies show correlations and interactions between peer substance use and genetic liability for substance use. However, none examined specific genes. Here we test the hypothesis that the nicotinic receptor genes CHRNA5 (rs16969968), CHRNA3 (rs578776), CHRNB3 (rs13277254) and CHRND (rs12466358) modify the risk for nicotine dependence associated with peer smoking.MethodsCases of current nicotine dependence [Fagerström Test for Nicotine Dependence (FTND)≥ 4] and smoking-exposed (smoked 100+ cigarettes life-time), but non-dependent controls (life-time FTND= 0) came from the Collaborative Genetic Study of Nicotine Dependence (n=2038). Peer smoking was assessed retrospectively for grades 9-12.ResultsPeer smoking and the four single nucleotide polymorphisms (SNPs) were associated with nicotine dependence. A statistically significant interaction was found between peer smoking and rs16969968 (P=0.0077). Overall risk of nicotine dependence was highest for the rs16969968 AA genotype. However, variance in nicotine dependence attributable to peer smoking was substantially lower among those with the AA genotype at rs16969968 than the lower-risk genotypes: AA=2.5%, GA/AG=11.2%, GG=14.2%; P≤ 0.004.ConclusionsPeer smoking had a substantially lower effect on nicotine dependence among those with the high-risk AA genotype at the functional SNP rs16969968 (CHRNA5) than among those with lower-risk genotypes. Such results highlight the possibility that given drug exposure those with specific genetic risks may be less affected by social contexts and intervention strategies focused upon social factors could have less influence on those at highest genetic risk.
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