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Effect of p53 polymorphisms on expression and progression of chronic hepatitis C

p53多态性对慢性丙型肝炎表达及进展的影响

基本信息

批准号：
12670320
负责人：
KANO Kazutaka
金额：
$ 1.98万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

Hepatitis C virus (HCV) is one of the leading cause of chronic hepatitis, and 20-30% of those infected with HCV develop cirrhosis, a condition preceding hepatocellular carcinoma (HCC). The natural course after HCV infection to the development of HCC is highly variable among individuals.Existence of somatic mutations of the tumor suppressor gene p53 in HCC has suggested an important role of the p53 on hepatocarcinogenesis. On the other hand, germline variation of p53 at codon 72 has been reported to associate with the susceptibility to various cancers. We previously reported that the p53 proline allele at codon 72 predominates in male subjects infected with HCV genotype 1b compared with non-infected controls. Since several investigations have reported the platelet count as an independent indicator for liver fibrosis and a valuable predictor for a risk of tumorigenesis, we examined the relationship between p53 polymorphism and the progression of thrombopenia by a longitudinal study of the cohort positive for HCV RNA.To investigate an impact of the tumor suppressor gene p53 polymorphism at codon 72 on the rapid progression of liver injury in chronic hepatitis C virus (HCV) infection, we followed up a cohort positive for HCV RNA between 1997 and 2002. The annual changes of the platelet count, which is a valuable predictor for the hepatic injury in HCV infection, in 54 subjects were compared among the p53 genotypes. The platelet decreased significantly faster in the proline homozygotes compared with the arginine homozygotes (p=0.046). In a multivariate model, the proline homozygous genotype was independently related to the impaired platelet count level (p=0.042 ; odds ratio=6.3). We conclude that the p53 proline homozygosity could be a risk factor for progression of HCV-induced thrombopenia.

丙型肝炎病毒（HCV）是慢性肝炎的主要原因之一，并且20-30%感染HCV的人发展肝硬化，这是肝细胞癌（HCC）之前的病症。HCV感染后肝癌发生发展的自然过程在个体间差异很大，肝癌中抑癌基因p53的体细胞突变的存在提示p53在肝癌发生中起重要作用。另一方面，已报道p53密码子72处的种系变异与对各种癌症的易感性相关。我们以前报道，p53脯氨酸等位基因在密码子72占主导地位的男性受试者感染HCV基因型1b与非感染的对照组相比。由于一些研究已经报道血小板计数是肝纤维化的独立指标和肿瘤发生风险的有价值的预测因子，我们通过一项HCV RNA阳性队列的纵向研究，检测了p53多态性与血小板减少症进展之间的关系。丙型肝炎病毒（HCV）感染，我们随访了1997年和2002年之间的HCVRNA阳性队列。对54例HCV感染者血小板计数的年变化进行了比较，血小板计数是HCV感染肝损伤的一个有价值的预测指标。脯氨酸纯合子的血小板减少速度明显快于精氨酸纯合子（p=0.046）。在多变量模型中，脯氨酸纯合基因型与受损血小板计数水平独立相关（p=0.042 ;比值比=6.3）。我们的结论是，p53脯氨酸纯合性可能是HCV引起的血小板减少症进展的危险因素。