The interaction between microsomal epoxide hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of environ mental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We inve stigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed usi ng generalized additive models and logistic regression, adjusting for relev ant covariates, There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity ge notype versus that of other genotypes combined was 1.00 [95% confidence int erval (CT), 0.73-1.34]. However, gene-environment interaction analyses reve aled that the ORs decreased as cumulative smoking (defined as square root o f 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 wh en pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42-1.00). When case s were stratified according to histological subtypes, the interaction betwe en mEH genotype and cumulative smoking was statistically significant (P < 0 .01) for the 222 squamous cell carcinoma cases, whereas it was not signific ant (P 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative ci garette smoking plays a pivotal role in the association between mEH polymor phisms 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 rela tively protective factor in heavy smokers.