||Background: Oxidative stress, generating from betel quid (BQ) chewing, cigarette smoking, and alcohol drinking; regulating by antioxidant-oxidant enzymes and dietary antioxidants seems to play a role in oral carcinogenesis. |
Objective: We aimed to examine the association between antioxidant-oxidant gene polymorphisms (CYBA, MnSOD, MPO, GPX1 and CAT), oral habits, and dietary antioxidants with the risk of oral squamous cell carcinoma (OSCC).
Design: A total of 381 pathologically proved primary OSCC cases and 598 healthy controls matched for age and sex were recruited between July 2003 and February 2008 in the hospital-based case-control study. Another 200 cancer-free controls frequency matched to 200 case patients on sex, age (±5 years), and pack-years of betel quid chewing. All subjects were interviewed to collect the data on socio-demographic variables, histories of BQ-chewing, tobacco smoking, alcohol drinking, and dietary antioxidant intake. Then, TaqMan assay were used to identify the genotype of functional or common allele tagging SNPs of each gene. The plasma total antioxidant capacities were measured by colorimetric assay.
Results: Higher intakes of vitamin C, vitamin E and lycopene together with gene polymorphisms (SOD2, GPX1, and CYBA) were associated with a decreased risk for OSCC in a trend-related manner. The risk of OSCC associated with CYBA genotype was modified by alcohol (Pinteraction = 0.04). Significant interactions were observed between BQ-chewing and SOD2 V16A (Pinteraction = 0.001), MPO G-463A (Pinteraction = 0.006) and CAT C3261T (Pinteraction = 0.002). GPx1 polymorphism interact with vitamin C and lutein/zeaxanthin to modify the risk of OSCC, respectively (Pinteraction = 0.023 and 0.006). In the combined analysis, a preventive relation appeared with subjects with seven “at risk genotype” (AOR, 0.62; 95% CI, 0.36-1.04) and those with three to six ones (AOR, 0.55; 95% CI, 0.33-0.94) compared with 8-9 ones in a trend-related manner (Ptrend = 0.042). It showed an interaction effect between BQ-chewing and the combination of antioxidant-oxidant gene polymorphisms with OSCC risk (Pinteraction = 0.001). The dose-dependent protective effect was related to the decreased numbers of “at risk genotypes” in lower intake of vitamin E (AOR, 0.54; 95% CI, 0.27-1.11 for 7 “at risk genotype”; AOR, 0.44; 95% CI, 0.21-0.90 for 3-6 “at risk genotype”; Ptrend = 0.035), and in higher intake of vitamin C (AOR, 0.33; 95% CI, 0.13-0.82 for 7 “at risk genotype”; AOR, 0.31; 95% CI, 0.12-0.73 for 3-6 “at risk genotype”; Ptrend = 0.047) and lycopene (AOR, 0.48; 95% CI, 0.20-1.14 for 7 “at risk genotype”; AOR, 0.38; 95% CI, 0.16-0.93 for 3-6 “at risk genotype”; Ptrend = 0.049). In stratification of the numbers of “at risk genotypes” of XRCC1 (XRCC1 R194W, R180H and R399B) for two groups (0-1 and 2-3 “at risk genotype” of XRCC1), the decreased risk of OSCC was observed with the decreasing number of “at risk genotype” in the antioxidant-oxidant genes (AOR, 0.34; 95% CI, 0.14-1.83 for 7 “at risk genotype”; AOR, 0.31; 95% CI, 0.14-0.74 for 3-6 “at risk genotype”; Ptrend = 0.032) among those with 0-1 “at risk genotype” of XRCC1. Significant interactions between MPO G-463A and alcohol consumption (Pinteraction 0.035), as well as between CYBA and lycopene intake in relation to OSCC risk (Pinteraction 0.036) respectively were found in those matched on BQ-chewing. Different from general population, the significant decreased risk of OSCC was observed among 2-3 “at risk genotypes” of XRCC1 with less “at risk genotype” (1-4) in the antioxidant-oxidant genes (AOR, 0.45; 95% CI, 0.25-0.82). In addition, we observed that subjects with seven to nine “at risk genotype” had significantly lower TAS level than those with less than 7 (P = 0.024) ones.
Conclusion: Antioxidant-oxidant genes and dietary antioxidants play an important role in cancer prevention. Dietary antioxidant intakes, alcohol and BQ-chewing may modify the protective magnitude of antioxidant genes. The synergistic effect of dietary antioxidant intakes and antioxidant-oxidant gene polymorphisms may decrease the impact of smoking, drinking or BQ-chewing on susceptibility to OSCC.