Abstract 2758: Genetic variability in tobacco-specific nitrosamine NNK to NNAL metabolism

Introduction: Tobacco-specific nitrosamine (TSNA) NNK metabolites NNAL and NNAL-gluc) together, (total NNAL), have recently been shown to be good predictors of lung cancer risk, years prior to diagnosis. However, the inter-individual variability in the metabolism of NNK evaluated by the total NNAL output could be explained in part by genetic variability in the genes of NNK metabolism. We sought to determine the contribution of several genetic polymorphisms to total NNAL output by a regression analysis of NNAL levels on genotyping results, controlling for measures of smoking, age and sex. Methods: The study subjects were derived from the Harvard/ Massachusetts General Hospital Lung cancer case-control study. We selected 92 subjects (39 lung cancer cases and 53 controls) smokers at time of diagnosis and urine collection (1992-1996). We tested 77 tagging SNPs in 16 genes related to NNK to NNAL metabolism. Using case status as a mediator, we tested for the association of each SNP with square-root (sqrt) transformed NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). Results: After a sqrt transformation, nicotine significantly predicted a 0.02 (0.015, 0.023) pmol/mg creatinine unit increase in NNAL for every ng/mg creatinine increase in nicotine at p = 2.85E-12. Three HSD11B1 SNPs, located in a 14kb region flanked by rs2235543 and rs3753519 in intron 1, were significantly associated with decreasing NNAL levels. Two of these SNPs, rs2235543 (p = 4.84E-08) and rs3753519 (p = 0.0017), passed multiple testing correction at FDR q value=1.07E-05 and 0.06 respectively. AKR1C4 rs7083869 G>A was also to be significantly associated with decreasing NNAL levels, p=0.019, FDR q=0.48. Conclusions: HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP correlated with the enzyme activity reducing variant rs17134592, L311V. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2758. doi:10.1158/1538-7445.AM2011-2758