探討人類宿主基因單一核苷酸多形性和男性慢性B型肝炎患者疾病進展的相關性

Abstract

慢性B型肝炎病毒感染是全球性的健康危害，尤其在亞洲地區，是一個相當重要的公共衛生議題。慢性B型肝炎患者長期肝臟發炎，會導致肝臟纖維化，併發肝硬化及肝細胞癌而導致死亡。根據統計，台灣的肝細胞癌目前高居癌症死因第二位。眾多學者的研究發現慢性B型肝炎患者的疾病進展變化廣泛，造成B型肝炎疾病進展的風險因子包括：病毒狀況、宿主本身的生理狀況及外在生活環境影響。過去的研究，對於病毒本身有相當多的研究，但對於與B型肝炎病毒感染的宿主因子卻瞭解有限。 最近一項日本研究，利用全基因（genome wide association study）掃描，比較慢性B型肝炎帶原者和非帶原者的差異性，結果顯示兩個單一核苷酸多形性（single nucleotide polymorphism，SNP），包括 HLA-DPA1的rs3077以及HLA-DPB1的rs9277535，都和B型肝炎的慢性化有關。而另一個中國的全基因掃描研究則探討慢性B型肝炎與肝細胞癌的關聯性，結果指出在一個基因插入序列(intron)的單一核苷酸多形性rs17401966於KIF1B基因染色體1p36.22的區段與B型肝炎相關的肝細胞癌具高度相關性。 因此，吾人將利用長期追蹤的慢性B型肝炎病毒感染男性患者的族群，區分為病例組（罹患肝細胞癌）及年紀、性別等相符合的對照組（不活動慢性B型肝炎帶原者），並使用case-control之研究設計來呈現不同關聯性。針對這兩組患者進行單一核苷酸多形性的rs3077、rs9277535以及rs17401966作基因分型，以釐清這幾個SNPs和慢性B型肝炎病程表現及預後的關係。 從我們的實驗結果顯示，HLA-DPA1（rs3077）的基因分型G allele相較於A allele有較高之危險對比值發生肝細胞癌【OR，1.39；95％信賴區間，1.10-1.74；P值為0.005（Additive model）】，而HLA-DPB1（rs9277535）的基因分型結果與發生肝細胞癌較無相關性。KIF1B基因（rs17401966）單一核苷酸多形性的基因分型A allele相較於G allele有較低之危險對比值發生肝細胞癌【OR，0.80；95％信賴區間，0.65-0.98；P值為0.029（Additive model）】。此外，HLA-DPA1（rs3077）的基因分型顯示罹患肝細胞癌之慢性B型肝患者雖未罹患肝硬化，相較於罹患肝細胞癌也罹患肝硬化之慢性B型肝患者反而有較高的危險對比值，容易發生肝細胞癌，這跟我們原先預期的結果不同。 我們的實驗結果與前人研究是一致的，之後我們將繼續探討其他人類宿主因子對B型肝炎病毒感染病程的影響，如檢測宿主與B型肝炎相關之細胞激素或是其他與B型肝炎相關之單一核苷酸多形性，例如：維生素D受體等等。假設某些SNP的基因型可以用來預測慢性B型肝炎患者疾病的進展，以後只要將這些SNPs作詳細的基因分型，便可以達到個人化醫療的部分目的。

Chronic hepatitis B virus (HBV) infection is a global health problem, especially in Asia. Chronic hepatitis B (CHB) patients may have long-term inflammation in the liver to cause fibrosis progression, cirrhosis and hepatocellular carcinoma (HCC). On the basis of health statistics, HCC is the second leading cause of cancer-related deaths in Taiwan. Previous studied indicated that disease progression in chronic hepatitis B patients varies widely. Risk factors affecting disease progression of HBV carriers include viral factors, host factors and environmental factors. Although several viral genomic factors have been identified to increase the risk of disease progression, little is known about the impact of host genetic factors on clinical outcomes of chronic hepatitis B patients in a recent Japanese study, GWAS approach was used to compare host genetic factors between HBV carriers and non-HBV carriers. Two single nucleotide polymorphisms (SNPs), rs3077 in HLA-DPA1 and rs9277535 in HLA-DPB1 were found to be highly associated with persistent HBV infection. Another GWAS study from China further identified an intronic SNP rs17401966 in KIF1B gene on chromosome 1p36.22, which was highly associated with HBV-related HCC. To address this interesting and important issue, a nested case-control study was conducted by using a long-term follow-up cohort of male chronic hepatitis B patients, in which every participant had a clear and defined phenotype. They consisted of the case group (patients with HCC) and the sex, age-matched control group (inactive carriers). Three SNPs (rs3077 in HLA-DPA1, rs9277535 in HLA-DPB1 and rs17401966 in KIF1B gene) were determined for both cases and controls. The impact of each SNP on the disease progression of chronic hepatitis B were analyzed. Our results showed that compared to A allele, G allele of rs3077 in HLA-DPA1 gene had a higher risk ratio for HCC (OR, 1.39; 95％CI, 1.10-1.74; P value = 0.005 (Additive model)). In contrast, rs9277535 genotypes in HLA-DPB1 gene were not associated with HBV-related HCC. Compared to G allele, A allele of rs17401966 in KIF1B gene had a lower risk ratio for HCC (OR, 0.80; 95％ CI, 0.65-0.98; P value = 0.029 (Additive model)). Further analysis showed that rs3077 genotype in HLA-DPA1 gene was associated with non-cirrhotic HCC. In summary, our findings are in line with previous data, and further studies will be continued to explore other host genetic factors determining the clinical outcomes of CHB patients, such as the SNPs in cytokine genes and vitamin D receptor gene. Clarifying the roles of viral and host genomic factors in disease progression of CHB may pave the way towards the goal of personalized medicine in patients with chronic HBV infection.