細胞毒T淋巴抗體-4基因與血管加壓素轉化酶基因多型性於南台灣原住民口腔癌前病變相關性之探討

Association of CTLA-4 gene and ACE gene polymorphism with oral precancerous lesion in Aborigines of Southern Taiwan

蔡忠勳(Chung-Shing Tsai)

指導教授 ： 謝天渝

高雄醫學大學/口腔醫學院/牙醫學研究所/碩士(2008年)

https://doi.org/10.6832/KMU.2008.00016

摘要

背景
癌前病變的早期診斷將有助於預知癌化的危險性，許多研究指出慢性發炎浸潤及自體免疫反應都與口腔黏膜病變有關。CTLA-4(細胞毒T淋巴抗體-4)基因為一種免疫調節因子，與T淋巴球活性調節有關係，是一種可以調控免疫機轉的物質 ; 而ACE(血管加壓素轉化酶)基因則參與許多組織的發炎反應，對於細胞的生長及重塑具有重要性。CTLA-4與ACE基因已被證實和許多免疫發炎疾病有著相關聯性，本篇研究主要目的在了解免疫與發炎相關基因多型性於高檳榔嚼食率的南台灣原住民中，對於口腔黏膜病變是否具有感受性增強的作用。
方法
我們收集了90位有口腔癌前病變與123位口腔黏膜健康者，皆是有長期(平均37.27年)咀嚼檳榔習慣的南台灣原住民，且在調控好各種口腔不良習癖狀況之下，去分析他們CTLA-4(A/G)基因和ACE(I/D)基因之基因多型性，並以Chi-square test與Conditional logistic regression等統計方法來作兩基因間的討論，試著去找出出免疫與發炎相關基因對於口腔黏膜變化時所扮演的角色。
結果
對於口腔癌前病變而言，CTLA-4的GG基因型相對於AA基因型呈現出較高的危險趨勢，然而不具有統計學上的意義(X2=5.899 , P=0.052 , OR : GG vs. AA=1.80 , 95% CI = 0.88-3.71)，而G對偶基因相對於A對偶基因，對於口腔癌前病變是有顯著影響的，且具有較高的危險性(X2=3.857 , P=0.0491 , OR : G vs. A=1.48 , 95% CI = 1.00-2.18)，因此了解到CTLA-4的GG基因型與G對偶基因，相對於AA基因型與A對偶基因來說，對於口腔癌前病變來說是屬於危險的因子 ; 而ACE的DD基因型(X2=8.818 , P=0.017 , OR : DD vs. II=3.19 , 95% CI=1.44-7.39)與D對偶基因(X2=8.218 , P=0.0041 , OR : D vs. I=1.77 , 95% CI=1.20-2.63)與對於口腔癌前病變皆具有顯著影響，因此了解到ACE的DD基因型與D對偶基因，相對於II基因型與I對偶基因來說，對於口腔癌前病變來說是屬於危險的因子。
最後，合併CTLA-4與ACE基因來作觀察的話，可發現同時擁有CTLA-4的GG基因型與ACE的DD基因型時，相對於兩種基因裡僅擁有一種口腔癌前病變危險基因型 (GG + ID/II) 與 (GA/AA + DD)，和同時擁有CTLA-4的AA基因型與ACE的II基因型的人，對於口腔癌前病變亦是具有較高的危險性與統計上顯著差別的(X2=10.008 , P=0.002 , OR =3.98 , 95% CI=1.67-10.11) ;當受測者同時擁有CTLA-4的G對偶基因與ACE的D對偶基因的受測者相對於其餘類型的對偶基因有較高的趨勢產生口腔癌前病變，且統計上是有意義的(X2=19.488 , P=0.0002 , OR =2.83 , 95% CI=1.53-5.37)，可以看出對於口腔癌前病變，當同時擁有兩種危險基因型或對偶基因時，會比單獨擁有一種危險基因型或對偶基因，危險性來得高。

結論
同時擁有CTLA-4的GG基因型和ACE的DD基因型會有較高的機會罹患口腔癌前病變，且同時擁有CTLA-4的G對偶基因和ACE的D對偶基因亦對於嚼食檳榔者的口腔黏膜是會有較高的危險性。對於口腔黏膜變化來說，會誘發發炎與免疫反應的因素，皆有可能導向惡性化的進展，除了加強檳榔戒除的宣導之外，利用基因來作腫瘤標記(tumor mark)的篩選，也是未來需要繼續努力的方向。

關鍵字

口腔癌 ； 檳榔 ； 原住民 ； 基因多型性

並列摘要

Background
Oral precancerous lesion (OPL) is a chronic disease that may affect the entire oral cavity. It has been indicated to be associated with inflammatory and immune reaction. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T-lymphocyte activation, it plays an important role in immune tolerance and energy. Angiotensin-converting enzyme (ACE) is expressed in a wide range of tissues. It may be involved in various steps of the inflammatory response. We therefore investigated the role of the CTLA-4 gene and ACE gene polymorphism in relation to the risk of OPL in an aboriginal population of southern Taiwan, which has a high prevalence of betel quid chewing.
Methods
We genotyped 90 betel quid chewers with OPL and 123 asymptomatic betel quid chewers matched for age, sex and oral habits status (betel quid chewing, smoking and drinking) for allelic determinants at the exon I +49 polymorphism site of the CTLA-4 gene and exon I +16 polymorphism site of the ACE gene by using restriction fragment length polymorphism (RFLP). The genotype and phenotype frequencies were evaluated by Chi-square test and conditional logistic regression.
Results
The frequency of homozygote for CTLA-4 G variant was higher in the case subjects than that of the controls and had a higher risk of OPL (43.3% vs. 27.6% ; P=0.052 ; odds ratio=1.80), but the findings were not statistically significant. In the allelic base analysis, the G allele was significantly higher in the case subjects than that of the controls and had a significant risk of OPL (60.00% vs. 50.41% ; P=0.0491 ; odds ratio=1.48). The frequency of homozygote for ACE D variant was significantly higher in the case subjects than that of the controls and was also significantly associated with a higher risk of OPL (38.9% vs. 26.0% ; P=0.017 ; odds ratio=3.19). In the allelic base analysis, the D allele was significantly higher in the case subjects than that of the controls and had a significant risk of OPL (62.78% vs. 48.78% ; P=0.0041 ; odds ratio=1.77). If we combine these two kinds of gene, the frequency of homozygote for CTLA-4 G variant combined with homozygote for ACE D variant was significantly higher in the case subjects than that of the controls and also significantly associated with a higher risk of OPL (21.11% vs. 7.32% ; P=0.019 ; odds ratio=3.98). In the allelic base analysis, the G allele of CTLA-4 combined with D allele of ACE was significantly higher in the case subjects than that of the controls and had a significant risk of OPL (36.11% vs. 17.48% ; P=0.0002 ; odds ratio=2.83).
Conclusion
Our study is the first to report the CTLA-4 G/G genotype combined with ACE D/D genotype, the same as the CTLA-4 G allele combined with ACE D allele confers an increased risk of OPL in aborigines of Taiwan. For the oral mucosal variation, immune and inflammatory reaction involvement may lead to cancerization. CTLA-4 gene A/G and ACE gene I/D polymorphism may be involved in the pathophysiology of immunologic derangement and inflammatory reaction in OPL. Further study is required to confirm these findings in populations of different races and these preliminary exploratory results should be confirmed in a larger study.

並列關鍵字

SCC ； Betel quid ； Aborigine ； polymorphism

參考文獻

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