Association of haplotypes of manganese superoxide dismutase (SOD2) with lung cancer risk

B76

Tobacco smoke produces reactive oxygen species (ROS) that can damage DNA, proteins, and lipids, eventually leading to cancer. Genetic variation in quenchers of ROS may therefore contribute to lung cancer risk. Manganese Superoxide Dismutase (SOD2) catalyzes the dismutation of superoxide radicals (a major form of ROS) into hydrogen peroxide and plays an important protective role against oxidative stress in lung tissues. Previous lung cancer association studies of SOD2 focused on one coding polymorphism, and results were not consistent across various populations. To comprehensively evaluate the role of genetic variation of SOD2 in lung cancer risk, we used data from the International HapMap project (CEPH genotypes) to assess linkage disequlibrium and choose tagSNPs that represent the common genetic variation in people with European ancestry. Three tagSNPs were identified in one block of high linkage disequilibrium that spans the entire SOD2 gene and 5 kb promoter region. The three tagSNPs were genotyped in 401 white lung cancer cases and 605 white controls using TaqMan genotyping assays and the ABI 7900 HT Sequence Detection System. Five-percent of samples were repeated for duplicate genotyping and there was 100% concordance of these quality controls with the original genotype call. Haplo.stats was used to estimate haplotype frequencies using the EM-algorithm and to perform the haplotype association analysis, adjusting for known covariates (age, gender, and pack-years). The genotype and haplotype frequencies matched previous estimates from HapMap Caucasians (CEPH). These haplotypes were not associated with lung cancer risk in an initial haplotype association test of all lung cancer histologies. However, the TCG haplotype (~6% in controls) is protective against adenocarcinoma (p-value =0.02) when stratifying subjects by histology, and in light-smokers (p-value = 0.01) when stratifying by median pack-years among smokers. This protective effect is most significant when examining light-smokers with adenocarcinoma (p-value = 0.005); in fact none of these cases (n=61) has the TCG haplotype. This study indicates that genetic variants of SOD2 may be protective against risk for adenocarcinoma, particularly in light-smokers.