- 學位論文
DNA甲基轉移酶與兒茶酚-O-甲基轉移酶基因多形性修飾抽菸、綠茶飲用與肺癌之相關
Genetic polymorphisms of DNA methyltransferase and catechol-O-methyltransferase modulate the associations of smoking, green tea consumption and lung cancer
摘要
抽菸 (smoking) 會導致DNA甲基化 (methylation) 以及腫瘤抑制基因 (tumor suppressor gene) 的過度甲基化，如此可能貢獻於後續的肺癌 (lung cancer) 發展。DNA甲基轉移酶3B (DNA methyltransferase 3B [DNMT3B]) 在DNA甲基化調控中至關重要，綠茶 (green tea) 亦被提出可能透過抑制其活性來降低癌症危險性。 在此，我們設計一項病例對照研究來探討是否DNMT3B -149基因多形性能夠調節抽菸所引發的肺癌危險性，抽菸以及綠茶飲用與此DNMT3B基因多形性的可能交互作用亦被評估。總計，190名肺癌病患與380名健康對照被納入本研究，問卷被執行來獲取人口學與生活型態之變項、以及肺癌家族史，DNMT3B -149基因型是以聚合酶鏈鎖反應 (polymerase chain reaction) 來辨識。結果顯示，抽菸、綠茶飲用、暴露於烹飪油煙、肺癌家族史以及DNMT3B -149基因型 (危險對比值 [odds ratio，OR] = 2.65；95%信賴區間 [confidence interval，C.I.] = 1.15-6.10) 皆是顯著地相關於肺癌發展。相較於攜帶DNMT3B -149 CT基因型之未抽菸者，攜帶DNMT3B -149 TT基因型之抽菸者呈現提升的肺癌危險性 (OR = 7.69，95% C.I. = 2.55-23.14)，抽菸與DNMT3B -149基因型對於肺癌危險性的交互作用是顯著的。然而，綠茶飲用與DNMT3B -149基因型的交互作用則未顯著。 進一步地，茶多酚 (tea polyphenols) 是強抗氧化劑，可藉由兒茶酚-O-甲基轉移酶 (catechol-O-methyltransferase [COMT]) 快速地被O-甲基化。因此，COMT的基因多形性可能修飾綠茶飲用與肺癌之相關。在本研究中，我們也評估綠茶飲用與COMT基因型對於肺癌危險的合併效應，237名肺癌病患與474名健康對照被納入，COMT基因型是以聚合酶鏈鎖反應來辨識。當攜帶COMT HL/LL基因型之綠茶飲用者被選取為參考組，攜帶COMT HH基因型之綠茶飲用者具有肺癌發生的較高危險性 (OR = 1.97；95% C.I. = 0.99-3.91)。在現今與曾經抽菸者之中，相較於攜帶COMT HL/LL基因型之綠茶飲用者，提升的肺癌危險性在攜帶COMT HH基因型之綠茶飲用者之中更為明顯 (OR = 5.84，95% C.I. = 1.75-19.45)。 因此，DNMT3B -149 TT基因型可能增加抽菸相關的肺癌危險性；在攜帶較大活性的COMT基因型之綠茶飲用者之中，兒茶素是較有效地被排除，進而獲得較少的保護效益以對抗肺癌的發展。
並列摘要
Smoking can cause increase of DNA methylation and hypermethylation of tumor suppressor genes, this possible contributing to subsequent lung cancer development. DNA methyltransferase 3B (DNMT3B) is crucial in regulation of DNA methylation and it has been proposed that green tea might lower cancer risk through inhibiting its activity. Here, we designed a case-control study to investigate whether the DNMT3B -149 genetic polymorphism could modulate lung cancer risk due to smoking. Possible interactions of smoking and green tea consumption with this DNMT3B genetic polymorphism were also assessed. A total of 190 lung cancer patients and 380 healthy controls were recruited. Questionnaires were administered to obtain data on sociodemographic and lifestyle variables, as well as family history of lung cancer. Genotypes for DNMT3B -149 were identified by polymerase chain reaction. Results showed smoking, green tea consumption, exposure to cooking fumes, family history of lung cancer, and the DNMT3B -149 genotype (odds ratio [OR] = 2.65; 95% confidence interval [C.I.] = 1.15-6.10) were all significantly associated with the development of lung cancer. Smokers carrying the DNMT3B -149 TT genotype were at elevated risk compared to non-smokers carrying DNMT3B -149 CT genotype (OR = 7.69; 95% C.I. = 2.55-23.14). Interaction of smoking with DNMT3B -149 genotypes was significant regarding lung cancer risk. However, interaction between green tea drinking and DNMT3B -149 genotypes was not significant. Further, tea polyphenols are strong antioxidants, which can be rapidly O-methylated by catechol-O-methyltransferase (COMT). Thus, it is possible that the genetic polymorphism of COMT can modulate the association of green tea consumption and lung cancer. In this study, we also evaluated the combined effect of green tea consumption and COMT genotypes on the risk of lung cancer; 237 lung cancer patients and 474 healthy controls were recruited, and genotypes for COMT were identified by polymerase chain reaction. When green tea drinkers carrying COMT HL/LL genotypes were selected as the reference group, drinkers carrying the COMT HH genotype had a higher risk for the development of lung cancer (OR = 1.97; 95% C.I. = 0.99-3.91). Among the current and ever smokers, the elevated risk for lung cancer was more apparent in green tea drinkers carrying the COMT HH genotype compared with green tea drinkers carrying COMT HL/LL genotypes (OR = 5.84; 95% C.I. = 1.75-19.45). Therefore, the DNMT3B -149 TT genotype might increase the smoking-associated lung cancer risk. Green tea drinkers with greater activity of the COMT genotype, whereby polyphenols are effectively excluded, will gain fewer protective benefits against lung cancer development.