人類白血球抗原-DP基因變異與B型肝炎病毒量及肝細胞癌之關係:家族研究

Abstract

研究背景: 在台灣大約有80%肝細胞癌(HCC)病例可歸因於B型肝炎病毒慢性感染。B型肝炎之高病毒量對於進展為肝細胞癌是個證據充分的危險因子。一篇全基因體關聯性研究定義出數個位在人類白血球抗原(HLA)-DP基因區上的單核苷酸多型性(SNPs)與慢性B型肝炎感染相關，並且已有許多研究驗證該發現。因此，本研究目在於利用家族研究來評估4個HLA-DP SNPs與B型肝炎病毒量控制及HCC危險性之關係。並且探討這之間的關係是否受到性別、病毒基因型及生活習慣等因素之潛在修飾作用影響。 材料方法: 我們使用先前已發表的家族研究中，共250個家庭、包含258個手足集合以評估HLA-DP SNPs在HBV病毒量控制所扮演的角色。而在這些家庭中，共有144對病例-未罹病手足配對進入HCC相關性分析。 結果: rs3077與男性早發HCC (定義為<50歲)有顯著相關(AG/AA vs. GG基因型OR=0.40，95% CI=0.17-0.94，P=0.0357)，但在女性中無顯著相關。其他SNPs並沒有觀察到類似的相關，而且也沒有發現這4個HLA-DP SNPs與晚發HCC有關。分析HLA-DP SNPs與HBV病毒量的部分，我們發現rs3128917帶有TG或TT基因型的人與HBV≧4.662 log copies/ml之高病毒量有負相關，其校正過後的OR值為0.64 (95% CI=0.46-0.89，p=0.0081)。而分層分析的部分，發現男性、感染HBV基因型C個案、HBeAg陰性個案、抽菸者及飲酒者也有類似的相關性。 結論: HLA-DP基因區上的變異在HCC家庭具有控制病毒量之作用，並且在進展為HCC上扮演著某些角色。

Background and Aims: In Taiwan, a proximately 80% of hepatocellular carcinoma (HCC) cases are attributable to chronic hepatitis B virus (HBV) infection. High level of HBV viral load has been well documented as a risk factor for progression to HCC. A genome-wide association study identified several single-nucleotide polymorphisms (SNPs) in HLA-DP region associated with chronic HBV infection, and this finding has been replicated in following studies. The aim of this study was to investigate the relationships between four HLA-DP SNPs and HBV viral load and HCC risk using a family-based study. The potential modification effects on these relationships by sex, viral genotype and lifestyle factors were also explored. Methods: We used data from a previously published family-based study involving a total of 250 families containing 258 sib sets to determine the role of HLA-DP SNPs in control of HBV viral load. Of these families, 144 case-unaffected sib pairs were included in the analysis of HCC. Results: rs3077 was significantly associated with early-onset HCC (defined as <50 years) in males (AG/AA vs. GG genotype: OR=0.40, 95% CI=0.17-0.94, p=0.0357) but not in females. No such association was observed for other SNPs, and there were no associations between all the four HLA-DP SNPs and late-onset HCC. In analysis of HLA-DP SNPs and HBV viral load, SNP rs3128917 carried TG or TT genotype was inversely associated with a high viral load of ≧4.662 log copies/ml, with an adjusted OR of 0.64 (95% CI=0.46-0.89, p=0.0081). In stratified analysis, this association was only observed in males, HBV genotype C group, HBeAg-negative subjects, cigarette smokers and alcohol drinkers. Conclusions: We suggest that the genetic variation in the HLA-DP region may be involved in the control of HBV viral load and play some role in the development of HCC in HCC families.