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

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Affiliations of authors: School of Experimental Psychology, University of Bristol, Bristol, UK (MRM); Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon CEDEX 08, France (MNT, PB); Division of Population Health, University College London, London, UK (RWM, JPC, BJJ, SE); Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (DP-M, JPC, AA); British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK (NS, SP); Department of Oncology, University of Oxford, Oxford, UK (ECJ); Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK (CR); Robertson Centre for Biostatistics, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK (PCDJ); Molecular Neurobiology Branch, NIH-IRP (NIDA), Baltimore, USA (DW, GRU); Division of Population Health Sciences and Education, St George's University of London, London, UK (PHW); School of Public Health, Imperial College, London, UK (PV, ER); HuGeF Foundation, Turin, Italy (PV); Woodlands Family Medical Centre, Stockton on Tees, UK (MNU); Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK (PA); University College London, London, UK (ADH); Division of Community-Based Sciences, University of Glasgow, Glasgow, UK (GW); MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE), School of Social and Community Medicine, University of Bristol, Bristol, UK (TMP, NJT, GDS).

Abstract

BackgroundTwo 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.MethodsWe 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.ResultsPooled 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 × 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 × 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).ConclusionsOur 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.