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A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol.

ABSTRACT: Genome-wide association studies have revealed an association between several loci in the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 and daily cigarette consumption. Recent studies have sought to refine this phenotype, and have shown that a locus within this cluster, marked primarily by rs1051730 and rs16969968, is also associated with levels of cotinine, the primary metabolite of nicotine. This association remains after adjustment for self-reported smoking, which suggests that even amongst people who smoke the same number of cigarettes there is still genetically-influenced variation in nicotine consumption. This is likely to be due to differences in smoking topography, that is, how a cigarette is smoked (e.g., volume of smoke inhaled per puff, number of puffs taken per cigarette). The aim of this study is to determine potential mediation of the relationship between the rs1051730 locus and cotinine levels by smoking topography.Adopting a recall-by-genotype design, we will recruit 200 adults from the Avon Longitudinal Study of Parents and Children on the basis of minor or major homozygote status at rs1051730 (100 in each genotype group). All participants will be current, daily smokers. Our primary study outcome measures will be measures of smoking topography: total volume of smoke (ml) inhaled per cigarette, total volume of smoke (ml) inhaled over of the course of one day, and salivary cotinine level (ng/ml).This study will extend our understanding of the biological basis of inter-individual variability in heaviness of smoking, and therefore in exposure to smoking-related toxins. The novel recall-by-genotype approach we will use is efficient, maximising statistical power, and enables the collection of extremely precise phenotypic data that are impractical to collect in a larger sample. The methods described within this protocol also hold the potential for wider application in the field of molecular genetics.

SUBMITTER: Ware JJ

PROVIDER: S-EPMC3900674 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol.

Ware Jennifer J JJ Timpson Nic N Davey Smith George G Munafò Marcus R MR

BMC medical genetics 20140122

<h4>Background</h4>Genome-wide association studies have revealed an association between several loci in the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 and daily cigarette consumption. Recent studies have sought to refine this phenotype, and have shown that a locus within this cluster, marked primarily by rs1051730 and rs16969968, is also associated with levels of cotinine, the primary metabolite of nicotine. This association remains after adjustment for self-reported smoking, whi ...[more]

PMID: 24451018

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Project description:IntroductionSmoking cessation is more than 50% heritable. Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design.Aims and methodsThis study tests single nucleotide polymorphism (SNP) associations with cessation during long-term follow-up throughout adulthood in women. The secondary aim tests whether genetic associations differ by smoking intensity. Associations between 10 SNPs in CHRNA5, CHRNA3, CHRNB2, CHRNB4, DRD2, and COMT and the probability of smoking cessation over time were evaluated in two longitudinal cohort studies of female nurses, the Nurses' Health Study (NHS) (n = 10 017) and NHS-2 (n = 2793). Participant follow-up ranged from 2 to 38 years with data collected every 2 years.ResultsWomen with the minor allele of either CHRNA5 SNP rs16969968 or CHRNA3 SNP rs1051730 had lower odds of cessation throughout adulthood [OR = 0.93, p-value = .003]. Women had increased odds of cessation if they had the minor allele of CHRNA3 SNP rs578776 [OR = 1.17, p-value = .002]. The minor allele of DRD2 SNP rs1800497 was associated with lower odds of cessation in moderate-to-heavy smokers [OR = 0.92, p-value = .0183] but increased odds in light smokers [OR = 1.24, p-value = .096].ConclusionsSome SNP associations with short-term smoking abstinence observed in prior studies were shown in the present study to persist throughout adulthood over decades of follow-up. Other SNP associations with short-term abstinence did not persist long-term. The secondary aim findings suggest genetic associations may differ by smoking intensity.ImplicationsThe results of the present study expand on previous studies of SNP associations in relation to short-term smoking cessation to demonstrate some of these SNPs were associated with smoking cessation throughout decades of follow-up, whereas other SNP associations with short-term abstinence did not persist long-term. The rate of relapse to smoking remains high for several years after quitting smoking, and many smokers experience multiple quit attempts and relapse episodes throughout adulthood. Understanding genetic associations with long-term cessation has potential importance for precision medicine approaches to long-term cessation management.

Project description:Multiple genome-wide and targeted association studies reveal a significant association of variants in the CHRNA5-CHRNA3-CHRNB4 (CHRNA5/A3/B4) gene cluster on chromosome 15 with nicotine dependence. The subjects examined in most of these studies had a European origin. However, considering the distinct linkage disequilibrium patterns in European and other ethnic populations, it would be of tremendous interest to determine whether such associations could be replicated in populations of other ethnicities, such as Asians. In this study, we performed comprehensive association and interaction analyses for 32 single-nucleotide polymorphisms (SNPs) in CHRNA5/A3/B4 with smoking initiation (SI), smoking quantity (SQ), and smoking cessation (SC) in a Korean sample (N = 8,842). We found nominally significant associations of 7 SNPs with at least one smoking-related phenotype in the total sample (SI: P = 0.015 approximately 0.023; SQ: P = 0.008 approximately 0.028; SC: P = 0.018 approximately 0.047) and the male sample (SI: P = 0.001 approximately 0.023; SQ: P = 0.001 approximately 0.046; SC: P = 0.01). A spectrum of haplotypes formed by three consecutive SNPs located between rs16969948 in CHRNA5 and rs6495316 in the intergenic region downstream from the 5' end of CHRNB4 was associated with these three smoking-related phenotypes in both the total and the male sample. Notably, associations of these variants and haplotypes with SC appear to be much weaker than those with SI and SQ. In addition, we performed an interaction analysis of SNPs within the cluster using the generalized multifactor dimensionality reduction method and found a significant interaction of SNPs rs7163730 in LOC123688, rs6495308 in CHRNA3, and rs7166158, rs8043123, and rs11072793 in the intergenic region downstream from the 5' end of CHRNB4 to be influencing SI in the male sample. Considering that fewer than 5% of the female participants were smokers, we did not perform any analysis on female subjects specifically. Together, our detected associations of variants in the CHRNA5/A3/B4 cluster with SI, SQ, and SC in the Korean smoker samples provide strong evidence for the contribution of this cluster to the etiology of SI, ND, and SC in this Asian population.

Project description:CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.

Dataset Information

A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol.

Publications

A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol.

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