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  • 學位論文

發炎相關基因多型性在胃癌前病變所扮演的角色

The role of inflammatory-related gene polymorphisms in gastric precancerous lesion

指導教授 : 卓夙航

摘要


胃癌是一種常見且致死率很高的癌症。基因多型性與幽門螺旋桿菌感染在許多的研究中已知會共同影響胃癌的發展。在這個過程中,幽門螺旋桿菌感染所引發的慢性發炎反應可能扮演這啟動胃癌發展的重要角色,而腸化生則是胃癌發展前的一個表徵。因此本研究主要想解決的問題在於腸化生的發生是否會受到幽門螺旋桿菌感染與發炎相關基因多型性(IL-6、IL-10、IL-1B、COX-2、VEGF、HIF-1A、GPX-1與GPX-3)的影響。在實驗設計上我們採用病例對照研究,腸化生組有353人,對照組有284人。對照組皆必須經過3年以上連續胃鏡與病組織切片檢查確定無腸化生的發生。在基因多型性的選擇上,我們選擇具有代表性的標誌單核苷酸多型性和具有功能的單核苷酸多型性。每個多型性位點的對偶基因分布透過Taqman基因型定型試驗與毛細管電泳被區分,我們也利用PHASE和Hap-clustering兩個程式做單套型的分析。 本研究一共在各個基因中選出27個多形性位點,大多數位點不論在病例組或對照組中都通過哈溫平衡的測試。最後統計的結果發現HIF-1A中的多型性位點SNP 14有達到統計上顯著差異。當CA基因型與CC參考基因型相比,其危險對比值為1.70 (95%信賴區間:1.20~2.41,P=0.003) ,而A對偶基因攜帶者與CC參考基因型相比其危險對比值有1.65 (95%信賴區間:1.18~2.30,P=0.003)。在單套型分析中,我們也發現HIF-1A基因中的4個多型性位點所形成的單套型,在調整完年齡與性別後,也達到統計上顯著差異(P=0.035)。但是以幽門螺旋桿菌感染狀態對腸化生進行分層分析,幽門螺旋桿菌感染並沒有與HIF-1A SNP 14基因型有交互作用。在其他的發炎相關基因多型性中,也並未發現與腸化生的發生有關。總結來說,在台灣族群中,HIF-1A基因可能會影響腸化生發展,但幽門螺旋桿菌的感染本身並不會加強HIF-1A的效能去影響腸化生的發生。

並列摘要


Gastric cancer is a common cancer with high mortality rate. Genetic polymorphisms can influence host susceptibility to gastric cancer. Helicobacter pylori (HP) infection has been recongnized as a major risk factor for gastric cancer through an chronic inflammatory process . Intestinal metaplasia (IM) is a major precancerous lesion for gastric cancer. The aim of the study is to evaluate the effect of HP infection and inflammatory–related gene(IL-6, IL-10, IL-1B, COX-2,VEGF, HIF-1A, GPX-1, GPX-3) polymorphisms in development of IM. A case-control study with 353 IM and 284 non-IM Taiwanese was conducted. All controls did not have IM pathological findings based on two or more consecutive biopsy examinations during a ?d 3-year follow-up. Tag single nucleotide polymorphisms (tSNPs) and functional polymorphisms were selected. The allelic discrimination of each polymorphism was determined by Taqman genotyping assay or capillary electrophoresis. We also performed the haplotype analysis by the PHASE and Hap-clustering programs. Among 27 polymorphisms, most of them were in Hardy- Weinberg equilibrium for either cases or controls. A statistical significance was found at HIF-1A SNP 14: the CA genotype of this SNP had an OR of 1.70 (95%CI:1.20~2.41, P=0.003) compared with the reference CC genotype. To compare with A carriers and CC genotype, the A carriers had an OR of 1.62 (95%CI:1.18~2.30,P=0.003). The haplotype analysis in HIF-1A polymorphisms also reached a statistical significance (p=0.035) after adjusting age and gender. However, HP infection did not have interaction with HIF-1A genotypes. There was no statistical significance between IM and other inflammatory-related gene polymorphisms. In conclusion, HIF-1A gene may independently play an important role in the development of IM in the Taiwanese population.

參考文獻


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