Sugiyama Masaya, Mizokami Masashi
The Research Center for Hepatitis and Immunoloy, National Center for Global Health and Medicine 1-7-1, Kohnodai, Ichikawa, Chiba 272-8516.
Uirusu. 2011 Jun;61(1):15-24. doi: 10.2222/jsv.61.15.
Based on the data and technology generated in previous international projects, such as the Human Genome Project and the HapMap, for the building of the common patterns of genetic variation in humans, a genome-wide association study (GWAS) to HCV infection was conducted to reveal genetic effects against treatment response or the induction of side effects. Single nucleotide polymorphisms (SNPs) associated with response to pegylated-interferon (PEG-IFN) and ribavirin (RBV) therapy were determined around IL-28B in chromosome 19, and the strong association was also observed in spontaneous viral clearance regardless of population. These data imply that an important interaction between HCV infection and IL-28B is critical for viral persistence or clearance. PEG-IFN and RBV therapy is associated with a range of treatment-limiting adverse effects. One of the frequent side effects induced by the combination therapy is haemolytic anaemia. The severe anaemia requires the reduction of the RBV dose, which could lead to treatment failure. Genetic variants around inosine triphosphatase gene (ITPA) were associated with heamolytic anaemia. Interestingly, the significant SNPs observed in Europe and the United States were not strongly associated with Japanese population although all significant SNPs were located around ITPA gene, suggesting that SNPs typing using individual population are required for the collection of precise data. These significant SNPs would be useful for prediction prior to treatment for individualized medicine.
基于此前国际项目（如人类基因组计划和国际人类基因组单体型图计划）所产生的数据和技术，为构建人类遗传变异的常见模式，开展了一项针对丙型肝炎病毒（HCV）感染的全基因组关联研究（GWAS），以揭示针对治疗反应或副作用诱导的遗传效应。在19号染色体上的白细胞介素-28B（IL-28B）周围确定了与聚乙二醇干扰素（PEG-IFN）和利巴韦林（RBV）治疗反应相关的单核苷酸多态性（SNP），并且在无论何种人群的自发病毒清除中也观察到了强关联。这些数据表明，HCV感染与IL-28B之间的重要相互作用对于病毒持续存在或清除至关重要。PEG-IFN和RBV治疗与一系列限制治疗的不良反应相关。联合治疗诱导的常见副作用之一是溶血性贫血。严重贫血需要减少RBV剂量，这可能导致治疗失败。肌苷三磷酸酶基因（ITPA）周围的遗传变异与溶血性贫血相关。有趣的是，尽管所有显著的SNP都位于ITPA基因周围，但在欧洲和美国观察到的显著SNP与日本人群的关联性不强，这表明为收集精确数据需要使用个体人群进行SNP分型。这些显著的SNP将有助于在个体化药物治疗前进行预测。
