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Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure

Lookup NU author(s): Dr Naweed Sattar, Professor Caroline Relton

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Abstract

Background Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. Methods We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. Results Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730-rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 x 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 x 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). Conclusions Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure.


Publication metadata

Author(s): Munafo MR, Timofeeva MN, Morris RW, Prieto-Merino D, Sattar N, Brennan P, Johnstone EC, Relton C, Johnson PCD, Walther D, Whincup PH, Casas JP, Uhl GR, Vineis P, Padmanabhan S, Jefferis BJ, Amuzu A, Riboli E, Upton MN, Aveyard P, Ebrahim S, Hingorani AD, Watt G, Palmer TM, Timpson NJ, Smith GD, EPIC Study Group

Publication type: Article

Publication status: Published

Journal: Journal of the National Cancer Institute

Year: 2012

Volume: 104

Issue: 10

Pages: 740-748

Print publication date: 25/04/2012

ISSN (print): 0027-8874

ISSN (electronic): 1460-2105

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/jnci/djs191

DOI: 10.1093/jnci/djs191


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