研究背景：由嚼食檳榔、抽煙及喝酒所造成的氧化壓力會受到抗氧化-氧化酶及抗氧化物飲食所調控，似乎在口腔癌的形成上扮演著重要的角色。
研究目標：本研究將探討抗氧化-氧化基因(CYBA, MnSOD, MPO, GPX1 and CAT)的多型性，菸酒檳榔習慣及抗氧化飲食對口腔鱗狀上皮細胞癌的風險關係。
實驗設計：我們執行一個以醫院為底的病例對照研究法，自2003年六月到2008年二月期間共完成收集381經病理診斷確認的原發性口腔上皮細胞癌病患和依性別、年齡所配對之598名健康配對。另外取200個無癌症的健康配對依性別、年齡及檳榔食用包年對200個口腔癌病患作配對。所有受試者均接受訪視以收集社會經歷和檳榔、菸、酒及抗氧化物飲食的使用情形。以鐵克曼定量聚合酶反應(TaqMan real-time PCR)測定各基因上的單一核苷酸基因多型性。而血漿中總抗氧化能力則是以光度色層分析法測量。
研究結果：攝食較高量的維生素C、E及茄紅素與抗氧化-氧化酶(SOD2、GPX1及CYBA)基因多型性共同時，口腔鱗狀上皮細胞癌的風險性會有減少的趨勢，且具有線性關係。而酒精會影響CYBA基因多型性對口腔鱗狀上皮細胞癌的風險(Pinteraction = 0.04)。嚼食檳榔則會對超氧化物歧化酶V16A(Pinteraction = 0.001)、骨髓過氧化酶G-463A(Pinteraction = 0.006)以及觸酶C3261T(Pinteraction = 0.002)有交互作用的關係。維生素C和葉黃素/玉米黃質會各自地去調節影響穀胱甘肽過氧化酶基因多型性對口腔鱗狀上皮細胞癌的風險(Pinteraction = 0.023 and 0.006)。在合併分析中，以8-9個「危險性基因型」被比上7個(校正勝算比0.62；95%信賴區間0.36-1.04)及3-6個(校正勝算比0.55；95%信賴區間0.33-0.94)，呈線性關係的保護效果。嚼食檳榔對合併型的抗氧化-氧化基因多型性在口腔鱗狀上皮細胞癌上出現了交互作用(Pinteraction = 0.001)。降低「危險性基因型」的個數對口腔癌有保護效果且呈現劑量效應的關係，特別是在攝食維生素E較少量的族群(校正勝算比0.54；95%信賴區間0.27-1.11→7個「危險性基因型」；校正勝算比0.44；95%信賴區間0.21-0.90→3-6個「危險性基因型」；Ptrend = 0.035)及維生素C(校正勝算比0.33；95%信賴區間0.13-0.82→7個「危險性基因型」；校正勝算比0.31；95%信賴區間0.12-0.73→3-6個「危險性基因型」；Ptrend = 0.047)和茄紅素(校正勝算比0.48；95%信賴區間0.20-1.14→7個「危險性基因型」；校正勝算比0.38；95%信賴區間0.16-0.93→3-6個「危險性基因型」；Ptrend = 0.049)攝食較多的族群。當以XRCC1的「危險性基因型」個數(XRCC1、R194W、R180H和R399B)做分層分析時，在含有0-1個XRCC1「危險性基因型」的族群中，發現到減少抗氧化-氧化基因的「危險性基因型」個數能降低口腔鱗狀上皮細胞癌的風險(校正勝算比0.34；95%信賴區間0.14-1.83→7個「危險性基因型」；校正勝算比0.31；95%信賴區間0.14-0.74→3-6個「危險性基因型」；Ptrend = 0.032)。在檳榔配對中，發現骨髓過氧化酶G-463A與飲酒(Pinteraction = 0.035)及CYBA與茄紅素(Pinteraction = 0.036)對口腔鱗狀上皮細胞癌的風險個別會有交互作用。不同於一般配對，在帶有XRCC1二到三個「危險性基因型」族群中，發現帶有抗氧化-氧化基因「危險性基因型」個數較少者能顯著的降低口腔鱗狀上皮細胞癌之風險。此外，結果顯示帶有7-9個「危險性基因型」的族群其血清總抗氧化力顯著地比帶有少於7個者低。
結論：抗氧化-氧化基因及抗氧化物飲食對癌症的預防扮演著重要的角色。而抗氧化飲食、酒精以及嚼食檳榔可能會調節影響抗氧化基因的保護效果。抗氧化飲食及基因多型性的加成效果可能降低菸、酒、檳榔對口腔鱗狀上皮細胞癌的易感性。

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.

Chapter 1
The Relationship of Polymorphisms in Antioxidant-oxidant Genes in General Population to OSCC Risk 13
1.1 Introduction 14
1.2 Specific Aims 20
1.3 Subjects and Methods 21
1.4 Results 25
1.5 Discussion 29
1.6 References 34
Chapter 2
The Relationship of Polymorphisms in Antioxidant-oxidant Genes in BQ-chewers to OSCC Risk 43
2.1 Introduction 44
2.2 Specific Aims 45
2.3 Subjects in betel-quid paired group 46
2.4 Results 47
2.5 Discussion 49
2.6 References 52
Chapter 3
Total Antioxidant Capacity 54
3.1 Introduction 55
3.2 Subjects and Methods 56
3.3 Results & Discussion 58
3.4 References 59
Tables 60
Chapter 4
Future Perspective 113
4.1 Specific Aims 114
4.2 Experimental Designs 115

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