Du Yan, Han Xue, Pu Rui, Xie Jiaxin, Zhang Yuwei, Cao Guangwen
Department of Epidemiology, Second Military Medical University, Shanghai, 200433, China.
Front Med. 2014 Jun;8(2):217-26. doi: 10.1007/s11684-014-0326-2. Epub 2014 Apr 21.
This study was designed to investigate the contribution of miRNA-122-binding site polymorphism at the IL-1A gene and its multiplicative interactions with hepatitis B virus (HBV) mutations in the risk of hepatocellular carcinoma (HCC). A total of 1021 healthy controls, 302 HBV surface antigen (HBsAg) seroclearance subjects, and 2011 HBsAg-positive subjects (including 1021 HCC patients) were enrolled in this study. Quantitative PCR was used to genotype rs3783553. HBV mutations were determined by direct sequencing. Multivariate logistic regression analyses were performed to test the associations of rs3783553, mutations, and their interactions with the risk of HCC. No significant association was found between rs3783553 and the risk of HCC among healthy controls, HBsAg seroclearance subjects, HBsAg-positive subjects without HCC, and all controls. Additionally, rs3783553 was not significantly associated with chronic HBV infection, liver cirrhosis, HBV e antigen seroconversion, abnormal alanine aminotransferase, and high viral load (> 10(4) copies/ml). However, the TTCA insertion allele of rs3783553 was significantly associated with an increased frequency of HBV C7A mutation compared with homozygous TTCA deletion carriers [(del/ins + ins/ins) vs. del/del, adjusted odds ratio (OR)= 1.48, 95% confidence interval (CI)= 1.09-2.02, P = 0.013]. Multiplicative interaction of rs3783553 with HBV preS deletion significantly reduced the risk of HCC in males, with an adjusted OR of 0.64 (95% CI = 0.42-0.98; P = 0.041) after age and HBV genotype were adjusted. Although rs3783553 did not significantly affect genetic susceptibility to HBV-related HCC, its variant allele may predispose the host to selecting HBV C7A mutation during evolution and significantly reduce the risk of HCC caused by HBV preS deletion. This study provides an insight into the complex host-virus interaction in HBV-induced hepatocarcinogenesis and is helpful in determining HBsAg-positive subjects who are likely to develop HCC.
本研究旨在调查白细胞介素-1A基因（IL-1A）上miRNA-122结合位点多态性及其与乙型肝炎病毒（HBV）突变的相乘相互作用在肝细胞癌（HCC）风险中的作用。本研究共纳入1021名健康对照者、302名HBV表面抗原（HBsAg）血清学清除者以及2011名HBsAg阳性者（包括1021名HCC患者）。采用定量PCR对rs3783553进行基因分型。通过直接测序确定HBV突变。进行多变量逻辑回归分析以检验rs3783553、突变及其相互作用与HCC风险的关联。在健康对照者、HBsAg血清学清除者、无HCC的HBsAg阳性者以及所有对照者中，未发现rs3783553与HCC风险之间存在显著关联。此外，rs3783553与慢性HBV感染、肝硬化、HBV e抗原血清学转换、丙氨酸氨基转移酶异常以及高病毒载量（>10⁴拷贝/ml）均无显著关联。然而，与纯合TTCA缺失携带者相比，rs3783553的TTCA插入等位基因与HBV C7A突变频率增加显著相关[（del/ins + ins/ins）与del/del相比，校正优势比（OR）=1.48，95%置信区间（CI）=1.09 - 2.02，P = 0.013]。rs3783553与HBV preS缺失的相乘相互作用在男性中显著降低了HCC风险，在调整年龄和HBV基因型后，校正OR为0.64（95%CI = 0.42 - 0.98；P = 0.041）。虽然rs3783553对HBV相关HCC的遗传易感性没有显著影响，但其变异等位基因可能使宿主在进化过程中倾向于选择HBV C7A突变，并显著降低由HBV preS缺失引起的HCC风险。本研究为HBV诱导的肝癌发生过程中复杂的宿主 - 病毒相互作用提供了见解，并有助于确定可能发生HCC的HBsAg阳性个体。
