陳建仁臺灣大學：流行病學研究所盧彥安Lu, Yan-AnYan-AnLu2007-11-272018-06-292007-11-272018-06-292005http://ntur.lib.ntu.edu.tw//handle/246246/56161目的： 本研究探討DNA修補相關基因的基因多形性與台灣女性肺腺癌危險性的獨立作用與交互作用，包括：hOGG1 Ser326Cys、XRCC1 Arg194Thr、XRCC1 Arg280His、XRCC1 Arg399Gln、Lig1 C170A、XPD Lys751Gln、hMLH1 G-93A、XRCC3 Thr241Met、p53 Arg72Pro與p21 Ser31Arg共10個多形性。 方法： 本研究為一病例對照研究，納入來自臺大醫院的女性肺腺癌病例共180名與臺大健檢中心的健康對照350名。基因多形性的鑑定利用聚合酵素連鎖反應以及Taqman即時聚合酵素連鎖反應為基礎的方式分析。各基因多形性的危險對比值和95%信賴區間估計以非條件式羅吉斯迴歸模式進行。 結果： 調整年齡、教育年數、吸煙與二手煙暴露、油煙暴露等因子後，XRCC1 399 Gln/Gln基因型相對於Arg/Arg或Arg/Gln基因型有2.21倍的危險性 (95% CI=1.2~4.2)；XPD 751 Gln/Gln基因型相對於Lys/Lys或Lys/Gln基因型有7.98倍的危險性 (95% CI=1.6~41.1)；p21 codon 31 Ser/Ser或Ser/Arg基因型相對危險性為Arg/Arg基因型的1.77倍(95% CI=1.1~3.0)。標記間交互作用分析則發現各標記的作用主要為獨立存在。基因多形性與環境暴露間的交互作用，也未具統計上的顯著性。 結論： 本研究發現DNA修補基因XRCC1 Arg399Gln、XPD Lys751Gln、p21 Ser31Arg多形性與肺腺癌的發生有關。Background DNA damage is an unavoidable result by exposing to intrinsic or extrinsic factors. DNA repair is an essential mechanism for maintaining integrity and accuracy of DNA, reduced DNA repair capacity may increase the susceptibility to cancer. We examined association among ten polymorphisms of DNA repair-related genes (hOGG1 Ser326Cys, XRCC1 Arg194Thr, XRCC1 Arg280His, XRCC1 Arg399Gln, Lig1 C170A, XPD Lys751Gln, hMLH1 G-93A, XRCC3 Thr241Met, p53 Arg72Pro, and p21 Ser31Arg) and lung adenocarcinoma risk among Taiwanese female. Methods A total of 180 female patients with lung adenocarcinoma and 350 healthy hospital control subject recruited in northern Taiwan from July 1997 until July 2000 provided DNA samples for genotype analysis. Genetic polymorphisms were analyzed by PCR-RFLP and Taqman assays. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results After adjusted for age, school year, tobacco exposure, and cooking fume exposure, the OR of developing adenocarcinoma was 2.21 (95% CI= 1.2~4.2) for XRCC1 399 Gln/Gln genotype (compared with other genotypes), 7.98 (95% CI=1.6~41.1) for XPD 751 Gln/Gln genotype (compared with other genotypes), and 1.77 (95% CI= 1.1~3.0) for p21 codon 31 Ser/Ser or Ser/Arg genotypes (compared with Arg/Arg genotype). Interactions between markers were not statistically significant, and so did interactions between markers and environmental exposures. Conclusion Our results suggests that the homozygous Gln alleles in codon 399 of the XRCC1 gene, homozygous Gln alleles in codon 751 of the XPD gene, and homozygous Ser alleles in codon 31 of the p21 gene might contribute to lung adenocarcinoma risk.CHAPTER 1. INTRODUCTION 1 1.1 Risk Factors 1 Cigarette Smoking 1 Passive Smoking 3 Domestic Cooking Fumes 3 Environmental Pollution 4 Previous Respiratory Disease 5 1.2 DNA Repair Mechanisms and polymorphisms 6 Base Excision Repair (BER) 8 hOGG1 8 XRCC1 10 Ligase1 10 Nucleotide Excision Repair (NER) 13 XPD 13 Mismatch Repair (MMR) 13 hMLH1 13 Double-strand-break Repair 16 XRCC3 16 Cell Cycle Control and Repair Regulation 18 p53 18 p21 18 CHAPTER 2. SUBJECTS AND METHODS 21 2.1 Case and Control Recruitment 21 2.2 Genotyping of DNA Repair Genes 22 2.3 Statistical Analysis 25 CHAPTER 3. RESULTS 26 3.1 Demographic Characteristics of Study Subjects 26 3.2 Ambient Air Pollution Exposure of Study Subjects 27 3.3 SNPs of DNA repair polymorphisms 29 3.4 Marker-Marker Interaction 33 3.5 Genetic Marker and Environmental Factor Interaction 37 CHAPTER 4. DISSCUSSION 39 References 45 Content of Tables Table 1.1 Studies on hOGG1 326 polymorphism and lung cancer risk 9 Table 1.2 Studies on XRCC1 polymorphisms and lung cancer risk 11 Table 1.3 Studies on Lig1 170 polymorphism and lung cancer risk 12 Table 1.4 Studies on XPD 751 polymorphism and lung cancer risk 14 Table 1.5 Studies on hMLH1 G-93A polymorphism and lung cancer risk 15 Table 1.6 Studies on XRCC3 241 polymorphism and lung cancer risk 17 Table 1.7 Studies on p53 72 polymorphism and lung cancer risk 19 Table 1.8 Studies on p21 31 polymorphism and lung cancer risk 19 Table 2.1 Sequence of Primer and Probe sets for Taqman technique 24 Table 3.1 Demographic characteristics of study subjects 26 Table 3.2 ORs and 95% CI of ambient air pollution exposure 28 Table 3.3 ORs and 95% CI of SNPs of DNA repair polymorphisms 30 Table 3.4 p-values based on chi-square test for marker-marker independence 34 Table 3.5 p-values based on regression model for marker-marker interaction term 34 Table 3.6 Gene-gene interaction between XRCC3 and p53 polymorphism 35 Table 3.7 ORs and 95% CI of combined SNPs of repair polymorphisms 36 Table 3.8 Tobacco exposure-stratified ORs of combined SNPs 38 Table 3.9 Cooking fume exposure-stratified ORs of combined SNPs 38 Table 3.10 Environmental exposure-stratified ORs of combined SNPs 38en-US女性肺腺癌DNA修補多形性female lung adenocarcinomaDNA repairpolymorphism[SDGs]SDG3thesis