Kathleen M Schieffer, Andrea Y Angstadt, Junjia Zhu, Philip Lazarus and Carla J Gallagher
Title: Associations between polymorphisms and haplotypes in the UDP-Glucuronosyl transferase 1A gene family with lung cancer risk. Background: Over 5,000 compounds have been identified in cigarette smoke, of which 73 are considered carcinogenic to either laboratory animals or humans by the International Agency for Research on Cancer. The UDPglucuronsyl transferases (UGTs) are Phase II drug-metabolizing enzymes that catalyze the metabolism of several cigarette smoke carcinogens for excretion. There are hundreds of genetic variants that span the nine genes in the UGT1A gene cluster, but the effect of UGT1A polymorphisms on lung cancer risk has not been studied in American Caucasians. This study hypothesized that UGT1A variants, either individually or as a haplotype, would be associated with lung cancer risk in American Caucasians. Methods and Findings: To examine the effect of genetic variation in the nine UGT1A genes on lung cancer risk, a comprehensive association and haplotype study was conducted using American Caucasian lung cancer cases and matched healthy controls on ninety-six tagSNPs. Known lung cancer risk factors including age, sex, smoking status, and pack-years of smoking were controlled for in all analyses. Multiple SNPs in the UGT1A gene cluster were associated with lung cancer risk in various stratified analyses before a multiple testing correction was applied. A significant association was found between two haplotypes in the UGT1A haplotype block 2 (rs7569014, rs7421795, rs1817154) and small cell carcinoma risk in American Caucasians. Multiple SNPs were found to affect lung cancer risk that did not remain significant following multiple testing correction. The UGT1A haplotype block 2 may be associated with small cell lung carcinoma. However, single SNP association studies did not yield significant results after multiple testing correction. Conclusions: UGT1A variants may play only a minor role in other lung cancer risk in American Caucasians; however, this needs to be confirmed in larger studies.