Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction.

Genome-wide association studies have identified variants on chromosome 15q25.1 that increase the risks of both lung cancer and nicotine dependence and associated smoking behavior. However, there remains debate as to whether the association with lung cancer is direct or is mediated by pathways related to smoking behavior. Here, the authors apply a novel method for mediation analysis, allowing for gene-environment interaction, to a lung cancer case-control study (1992-2004) conducted at Massachusetts General Hospital using 2 single nucleotide polymorphisms, rs8034191 and rs1051730, on 15q25.1. The results are validated using data from 3 other lung cancer studies. Tests for additive interaction (P = 2 × 10(-10) and P = 1 × 10(-9)) and multiplicative interaction (P = 0.01 and P = 0.01) were significant. Pooled analyses yielded a direct-effect odds ratio of 1.26 (95% confidence interval (CI): 1.19, 1.33; P = 2 × 10(-15)) for rs8034191 and an indirect-effect odds ratio of 1.01 (95% CI: 1.00, 1.01; P = 0.09); the proportion of increased risk mediated by smoking was 3.2%. For rs1051730, direct- and indirect-effect odds ratios were 1.26 (95% CI: 1.19, 1.33; P = 1 × 10(-15)) and 1.00 (95% CI: 0.99, 1.01; P = 0.22), respectively, with a proportion mediated of 2.3%. Adjustment for measurement error in smoking behavior allowing up to 75% measurement error increased the proportions mediated to 12.5% and 9.2%, respectively. These analyses indicate that the association of the variants with lung cancer operates primarily through other pathways.

[1]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[2]  Paul Brennan,et al.  Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. , 2010, Journal of the National Cancer Institute.

[3]  D. Christiani,et al.  Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. , 2002, Cancer research.

[4]  Raymond J. Carroll,et al.  Bias Analysis and SIMEX Approach in Generalized Linear Mixed Measurement Error Models , 1998 .

[5]  T. Thorgeirsson,et al.  Commentary: gene-environment interactions and smoking-related cancers. , 2010, International journal of epidemiology.

[6]  Tariq Ahmad,et al.  Meta-analysis and imputation refines the association of 15q25 with smoking quantity , 2010, Nature Genetics.

[7]  P. Dasgupta,et al.  Nicotinic acetylcholine receptors in cancer: multiple roles in proliferation and inhibition of apoptosis. , 2008, Trends in pharmacological sciences.

[8]  K. Mossman The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[9]  Mark J. van der Laan,et al.  Estimation based on case-control designs with known prevalence probability. , 2008 .

[10]  D. Servent,et al.  Multiple roles of nicotine on cell proliferation and inhibition of apoptosis: implications on lung carcinogenesis. , 2008, Mutation research.

[11]  S. Heath,et al.  Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals. , 2010, International journal of epidemiology.

[12]  C. Gieger,et al.  Sequence variants at CHRNB 3 – CHRNA 6 and CYP 2 A 6 affect smoking behavior , 2010 .

[13]  Norman E. Breslow,et al.  Logistic regression for two-stage case-control data , 1988 .

[14]  Maarit Tiirikainen,et al.  Smokers with the CHRNA lung cancer-associated variants are exposed to higher levels of nicotine equivalents and a carcinogenic tobacco-specific nitrosamine. , 2008, Cancer research.

[15]  T. VanderWeele Bias Formulas for Sensitivity Analysis for Direct and Indirect Effects , 2010, Epidemiology.

[16]  E. C. Hammond,et al.  Smoking and lung cancer: recent evidence and a discussion of some questions. , 1959, Journal of the National Cancer Institute.

[17]  L. Bierut,et al.  Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking , 2008, Cancer Epidemiology Biomarkers & Prevention.

[18]  RONALD A. FISHER,et al.  Lung Cancer and Cigarettes? , 1958, Nature.

[19]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[20]  Mark J van der Laan,et al.  The International Journal of Biostatistics Direct Effect Models , 2011 .

[21]  Chapel Hill Genome-wide meta-analyses identify multiple loci associated with smoking behavior. , 2010 .

[22]  William Wheeler,et al.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD , 2010, PLoS genetics.

[23]  J. Minna Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer. , 2003, The Journal of clinical investigation.

[24]  Nicholas G Martin,et al.  Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. , 2007, Human molecular genetics.

[25]  Inês Barroso,et al.  Meta-analysis and imputation refines the association of 15q25 with smoking quantity , 2010, Nature Genetics.

[26]  Tatiana Foroud,et al.  Variants in nicotinic receptors and risk for nicotine dependence. , 2008, The American journal of psychiatry.

[27]  D. Grobbee,et al.  Estimating interaction on an additive scale between continuous determinants in a logistic regression model. , 2007, International journal of epidemiology.

[28]  M. Graffar [Modern epidemiology]. , 1971, Bruxelles medical.

[29]  P. Muglia,et al.  α-5/α-3 nicotinic receptor subunit alleles increase risk for heavy smoking , 2008, Molecular Psychiatry.

[30]  N. Chatterjee,et al.  Intermediacy and gene-environment interaction: the example of CHRNA5-A3 region, smoking, nicotine dependence, and lung cancer. , 2008, Journal of the National Cancer Institute.

[31]  Zhifu Sun,et al.  Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. , 2010, The Lancet. Oncology.

[32]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[33]  Stephen J. Chanock,et al.  Genomics: When the smoke clears ... , 2008, Nature.

[34]  Christopher I Amos,et al.  The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. , 2008, Journal of the National Cancer Institute.

[35]  Stijn Vansteelandt,et al.  Odds ratios for mediation analysis for a dichotomous outcome. , 2010, American journal of epidemiology.

[36]  S Lemeshow,et al.  Confidence interval estimation of interaction. , 1992, Epidemiology.

[37]  R C Frecker,et al.  Measuring the heaviness of smoking: using self-reported time to the first cigarette of the day and number of cigarettes smoked per day. , 1989, British journal of addiction.

[38]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[39]  Christopher I. Amos,et al.  Mediating effects of smoking and chronic obstructive pulmonary disease on the relation between the CHRNA5‐A3 genetic locus and lung cancer risk , 2010, Cancer.