Association of polymorphisms in the heparanase gene (HPSE) with hepatocellular carcinoma in Chinese populations

Abstract Heparanase activity is involved in cancer growth and development in humans and single nucleotide polymorphisms (SNPs) in the heparanase gene (HPSE) have been shown to be associated with tumors. In this study, we investigated whether SNPs in HPSE were a risk factor for hepatocellular carcinoma (HCC) by undertaking a comprehensive haplotype-tagging, case-control study. For this, six haplotype-tagging SNPs (htSNPs) in HPSE were genotyped in 400 HCC patients and 480 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A log-additive model revealed significant correlations between the HPSE polymorphisms rs12331678 and rs12503843 and the risk of HCC in the overall samples (p = 0.0046 and p = 0.0055). When the analysis was stratified based on hepatitis B virus (HBV) carrier status, significant interactions between rs12331678 and rs12503843 and HBV were observed. Conditional logistic regression analysis for the independent effect of one significant SNP suggested that rs12331678 or rs12503843 contributed an independent effect to the significant association with the risk of HCC, respectively. Our findings suggest that the SNPs rs12331678 and rs12503843 are HCC risk factors, although the potential functional roles of these two SNPs remain to be fully elucidated.

摘要 乙酰肝素酶（heparanase）活性参与人类肿瘤的发生与发展，而乙酰肝素酶基因（heparanase gene, HPSE）中的单核苷酸多态性（single nucleotide polymorphisms, SNPs）已被证实与肿瘤相关。本研究通过开展全面的单倍型标签病例对照研究，探讨乙酰肝素酶基因中的单核苷酸多态性是否为肝细胞癌（hepatocellular carcinoma, HCC）的危险因素。为此，本研究采用聚合酶链反应-限制性片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP）分析方法，对400例肝细胞癌患者与480例对照个体的乙酰肝素酶基因中的6个单倍型标签单核苷酸多态性（haplotype-tagging SNPs, htSNPs）进行基因分型。对数加性模型分析显示，在全部研究样本中，乙酰肝素酶基因多态性位点rs12331678与rs12503843与肝细胞癌发病风险存在显著相关性（p=0.0046，p=0.0055）。按乙型肝炎病毒（hepatitis B virus, HBV）携带状态进行分层分析后，观察到rs12331678、rs12503843与HBV之间存在显著交互作用。针对单个显著单核苷酸多态性的独立效应开展条件logistic回归分析结果显示，rs12331678与rs12503843分别对肝细胞癌发病风险的显著关联具有独立贡献。本研究结果表明，rs12331678与rs12503843这两个单核苷酸多态性位点可作为肝细胞癌的危险因素，不过这两个位点的潜在生物学功能仍有待全面阐明。