ABSTRACT Tobacco smoking is a risk factor for colorectal cancer and adenomas. To clarify the effect of genetic factors on the risk for tobacco-related colorectal tumors in a Japanese population, we performed a case-control study on 300 patients with two or more tumors and 181 healthy controls; all were genotyped for CYP2A6*4, CYP2A6*7 and CYP2A6*9. Cigarette smoking increased colorectal tumor risk (trend-test P < 0.0000005). Current smokers plus ex-smokers (ever-smokers) with the CYP2A6*4/*4 genotype (whole gene deletion) showed the lowest risk among smokers [odds ratio (OR), 0.17; 95% confidence interval (CI), 0.05 - 0.62 compared to ever-smokers with the wild-type CYP2A6*1/*1]. When the participants were classified into four phenotype groups based on estimated CYP2A6 activity [i.e., normal (*1/*1), intermediate (heterozygotes for the *1 and a variant allele), slow (heterozygotes and homozygotes for variant alleles except for *4/*4) and poor (*4/*4)], the ORs (95% CIs) in ever-smokers of the normal, intermediate, slow and poor groups were 6.75 (2.73 - 16.76), 4.59 (2.10 - 10.06), 3.89 (1.69 - 8.95) and 1.17 (0.31 - 4.40), respectively, compared with never-smokers with normal CYP2A6 activity. The susceptibility to colorectal tumors was dependent on the predicted phenotype among ever-smokers (trend-test P = 0.015), but not among never-smokers (trend-test P = 0.47). Stratifying the subjects with respect to cumulative tobacco exposure and estimated CYP2A6 activity, we found the highest risk of colorectal tumors in subjects with higher CYP2A6 activity and higher cumulative tobacco exposure (trend-test P = 0.000023); the lowest risk was found in subjects with the lowest estimated CYP2A6 activity independent of tobacco exposure (trend-test P = 1.00). These results suggest that the gene-environment interaction (i.e. , the CYP2A6-smoking interaction) strongly affects the individual susceptibility to tobacco-related colorectal tumors.
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