Department of Gastroenterology and Hepatology Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.
Hepatol Res. 2010 Nov;40(11):1063-71. doi: 10.1111/j.1872-034X.2010.00741.x.
Host genetic variants leading to inosine triphosphatase (ITPA) deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in chronic hepatitis C patients receiving ribavirin. In this study, we evaluated the clinical significance of ITPA variants in Japanese hepatitis C patients who were treated with pegylated interferon plus ribavirin.
In this multicenter retrospective cross-sectional study, 474 hepatitis C patients were enrolled who were treated with pegylated interferon plus ribavirin in four geographically different hospitals in Japan. Patients were grouped according to hemoglobin decline of more than 3 g/dL at week 4. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs6051702, rs1127354) were genotyped.
A functional SNP, rs1127354, within the ITPA exon was strongly associated with protection against anemia with only one (0.8%) in 129 patients with the ITPA minor variant A developing severe anemia (P=5.9×10(-20) ). For rs6051702, which had significant association in European-Americans, significant but weak association with severe hemoglobin reduction was found in Japanese (P= 0.009). In patients excluding genotype 1b and high viral load, those with the ITPA minor variant A achieved significantly higher sustained viral response rate than those with the major variant (CC) (96% vs 70%, respectively, P= 0.0066).
ITPA SNP, rs1127354, is confirmed to be a useful predictor of ribavirin-induced anemia in Japanese patients. Patients with the ITPA minor variant A (~ 27%) have an advantage in pegylated interferon plus ribavirin-based therapies, due to expected adherence of ribavirin doses, resulting in a higher viral clearance rate.
导致肌苷三磷酸酶（ITPA）缺乏的宿主遗传变异，这种情况被认为没有临床意义，可预防接受利巴韦林治疗的慢性丙型肝炎患者发生溶血性贫血。在这项研究中，我们评估了接受聚乙二醇干扰素联合利巴韦林治疗的日本丙型肝炎患者中 ITPA 变异的临床意义。
在这项多中心回顾性横断面研究中，共纳入了 474 例在日本四个地理位置不同的医院接受聚乙二醇干扰素联合利巴韦林治疗的丙型肝炎患者。根据第 4 周时血红蛋白下降超过 3 g/dL 的情况将患者分组。对 ITPA 基因内或附近的两个单核苷酸多态性（SNP）（rs6051702、rs1127354）进行基因分型。
ITPA 外显子内的一个功能性 SNP（rs1127354）与贫血的保护作用密切相关，在 129 例 ITPA 次要变异 A 患者中只有 1 例（0.8%）发生严重贫血（P=5.9×10(-20)）。在欧洲裔人群中具有显著相关性的 rs6051702 在日本人中也与严重血红蛋白减少显著相关（P=0.009）。在排除基因型 1b 和高病毒载量的患者中，携带 ITPA 次要变异 A 的患者获得持续病毒学应答的比例显著高于携带主要变异（CC）的患者（分别为 96%和 70%，P=0.0066）。
ITPA SNP（rs1127354）被证实可作为日本患者利巴韦林诱导性贫血的有用预测因子。携带 ITPA 次要变异 A（~27%）的患者在聚乙二醇干扰素联合利巴韦林治疗中具有优势，因为预计会遵守利巴韦林的剂量，从而提高病毒清除率。
