title: Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk.
abstract: Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.
authors: Centre for Addiction and Mental Health, Department of Psychiatry, Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Bldg, Rm 4326, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: Catherine A
authors: CA
authors: Wassenaar
authors: Qiong
authors: Q
authors: Dong
authors: Qingyi
authors: Q
authors: Wei
authors: Christopher I
authors: CI
authors: Amos
authors: Margaret R
authors: MR
authors: Spitz
authors: Rachel F
authors: RF
authors: Tyndale
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015986:Confounding Factors, Epidemiologic; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009602:Nitrosamines / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics*; D011795:Surveys and Questionnaires; D044465:White People / Q000235:genetics*
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D009419:Nerve Tissue Proteins; D009602:Nitrosamines; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human; C585710:CYP2A6 protein, human