台灣人類白血球抗原DRB1基因多形性、人類疣瘤病毒與子宮頸癌之研究

Abstract

背景：人類疣瘤病毒是子宮頸癌的主要危險因子，而第二型人類白血球抗原是將外來抗原呈現給T細胞辨識進而產生一連串的免疫反應，第二型人類白血球抗原基因的多形性，可能影響人類疣瘤病毒持續感染進而導致子宮頸癌。故本研究欲探討人類白血球抗原DRB1基因的多形性在人類疣瘤病毒的作用下對婦女產生子宮頸癌的影響。

方法：本研究為病例對照研究法（case-control study），於台灣七個鄉鎮的長期社區篩檢計畫中，從1991年到2003年止，連結癌症登記檔、死亡檔、重大傷病檔取得89名子宮頸癌病例，包含原位癌與侵襲癌，以年齡、地區、採檢前後六個月為配對條件，共收304名的對照個案。人類白血球抗原DRB1的檢驗方式為聚合酵素連鎖反應為基礎的序位寡核苷酸特異探針分析方式。以G檢定或費歇爾精確檢定（當細格數小於5）計算對位基因之頻率及分佈差異性檢定，並在配對的條件下進行HLA DRB1之對偶基因與子宮頸癌的相關危險性的估計，採用條件式邏輯式迴歸分析(conditional logistic regression)，計算出對比值比率（odds ratio, OR）及95%信賴區間（confidence interval, CI）。

結果：對照組中帶有DRB1*1401在感染人類疣瘤病毒有顯著危險，OR值為4.4 (95% CI=1.6-11.9)；子宮頸癌病例與對照比較，DRB1*0303與DRB1*1101在子宮頸癌有顯著的危險，OR值分別為7.4 (95% CI=1.5-37.3)、2.2(95% CI=1.3-3.6)；控制人類疣瘤病毒的影響後，DRB1*1101仍有顯著相關，OR值為2.5 (95% CI=1.1-6.0)；高危險群的病例對照比較中，DRB1*1202有顯著的保護作用，OR值為0.2 (95% CI=0.1-0.7)；人類疣瘤病毒16相關型別病例對照比較中，DRB1*1202仍有顯著的保護作用，OR值為0.2 (95% CI=0.1-0.7)。

Background: Infection with human papillomavirus (HPV) is the major risk factor for cervical cancer. HLA II molecules could present foreign antigens to T cells, then inducing a series of immune responses. The highly polymorphisms of HLA II genes may affect the persistent infection of HPV, further leading to the occurrences of cervical cancer. This study aimed to investigate the association of HLA DRB1 genetic polymorphisms and cervical cancer in HPV infection.

Methods: This study is a case-control study. During 1991 to 2003, we recruited 89 cervical cancer patients (including in situ and invasive cancer) from a linkage with National Cancer Registry, National Death Certification and National Cervical Neoplasia Registry in the large-scale community-based cervical neoplasia screening project of seven townships. We recruited 304 controls which matched by age, residential township and sampling time. HLA typing was done by polymerase chain reaction-based method, followed by sequence-specific oligonucletide probe hybridization. G test or Fisher’s exact test were used to examine the differences in the frequency distributions between cases and controls. Conditional and unconditional logistic regression models were used to assess the association between HLA-DRB1 genes and cervical cancer with odds ration (ORs) and 95% confidence interval (CIs).

Result: DRB1*1401 was found to be associated with HPV infection (OR, 4.4; 95% CI, 1.6-11.9). Compared HPV cases with controls, DRB1*0303 (OR, 7.4; 95%CI, 1.5-37.3) and DRB1*1101 (OR, 2.2; 95%CI, 1.3-3.6) were found to be associated with cervical cancer. DRB1*1101 were still found to be associated with cervical cancer after adjusting the effects of HPV infection (OR, 2.5; 95% CI. 1.1-6.0). Compared the high-risk HPV cases with controls, DRB1*1202 significantly decreased the risks of cervical cancer (OR, 0.2; 95% CI. 0.1-0.7). Compared HPV 16 relative type cases with controls, DRB1*1202 also significantly decreased the risks of cervical cancer (OR, 0.2; 95% CI. 0.1-0.7).