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The Interaction between Microsomal Epoxide Hydrolase Polymorphisms and Cumulative Cigarette Smoking in Different Histological Subtypes of Lung Cancer¹

Occupational Health Program, Departments of Environmental Health [W. Z., L. L. X., D. P. M., L. S., D. C. C.] and Biostatistics [S. W. T.], Harvard School of Public Health, Boston, Massachusetts 02115 and Departments of Hematology-Oncology [G. L., T. J. L.], Medicine and Thoracic Surgery Unit, Surgery [J. C. W.], and Pulmonary and Critical Care Unit [D. C. C.], Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of environmental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We investigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity genotype versus that of other genotypes combined was 1.00 [95% confidence interval (CI), 0.74–1.34]. However, gene-environment interaction analyses revealed that the ORs decreased as cumulative smoking (defined as square root of pack-years) increased. When pack-years = 0, the OR was 1.89 (95% CI, 1.08–3.28). When pack-years = 28.5, the OR was 1.00 (95% CI, 0.76–1.32), and when pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42–1.00). When cases were stratified according to histological subtypes, the interaction between mEH genotype and cumulative smoking was statistically significant (P < 0.01) for the 222 squamous cell carcinoma cases, whereas it was not significant (P = 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative cigarette smoking plays a pivotal role in the association between mEH polymorphisms and lung cancer risk, altering the direction of risk (in the case of the very low activity genotype) from a risk factor in nonsmokers to a relatively protective factor in heavy smokers.

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