Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C.
Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C.
复制标题
ITPA基因变异和血清利巴韦林浓度与聚乙二醇干扰素-α加利巴韦林治疗慢性丙型肝炎中血细胞下降的关系。
DOI：
10.1007/s12072-012-9363-6
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发表时间：
2013
期刊：
影响因子：
6.6
通讯作者：
Ochanomizu Liver Conference Study Group
中科院分区：
文献类型：
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作者：
Nakagawa M;Sakamoto N;Watanabe T;Nishimura-Sakurai Y;Onozuka I;Azuma S;Kakinuma S;Nitta S;Kiyohashi K,Kusano-Kitazume A;Murakawa M;Yoshino K;Itsui Y;Tanaka Y;Mizokami M,Watanabe M;Ochanomizu Liver Conference Study Group
背景遗传变异导致的肌苷三磷酸酶（ITPA）缺乏可保护接受利巴韦林治疗的慢性丙型肝炎患者免于溶血性贫血。ITPA基因变异和血清利巴韦林浓度之间的关系进行了分析，与血细胞减少和剂量减少聚乙二醇干扰素（PEG-IFN）或ribavirin.Patients和methodsA共300例丙型肝炎患者与PEG-IFN加利巴韦林进行了分析。在ITPA中测定遗传多态性，并在治疗期间和治疗结束后每4周分析一次血细胞相对于基线的定量减少。下降血红蛋白（Hb）或血小板（PLT）水平在第4周相比，基线也进行了评估，根据利巴韦林concentration.ResultsPatients与theITPA-CA/AA基因型表现出较低程度的Hb减少整个治疗比那些与theITPA-CC基因型和显着差异，平均Hb减少被发现在第4周（CA/AA-1.0与CC-2.8，p < 0.001）。在治疗早期，ITPA-CC基因型患者的平均血小板计数下降明显低于ITPA-CA/AA基因型患者（第4周和第8周p< 0.001）。ITPA-CA/AA基因型患者不太可能发生贫血，无论利巴韦林的浓度如何。基线PLT计数低于130 × 103/μl的患者获得持续病毒学应答（SVR）的倾向明显降低，尤其是ITPA-CA/AA基因型患者。ITPA基因变异没有提取的多变量分析作为一个重要的预测SVR.ConclusionsDespite事实，ITPA变异不太可能发展贫血，低基线血小板计数的患者难以治疗，尤其是那些与theITPA-CA/AA基因型。这些结果可能提供了一个有价值的药物遗传学诊断工具的定制剂量，以尽量减少药物引起的不良事件。
BackgroundGenetic variation leading to inosine triphosphatase (ITPA) deficiency protects chronic hepatitis C patients receiving ribavirin against hemolytic anemia. The relationship betweenITPAgene variation and serum ribavirin concentration was analyzed in association with a reduction in blood cells and dose reduction of pegylated interferon (PEG-IFN) or ribavirin.Patients and methodsA total of 300 hepatitis C patients treated with PEG-IFN plus ribavirin were analyzed. Genetic polymorphisms were determined inITPAand the quantitative reduction in blood cells from the baseline was analyzed every 4 weeks for the duration of treatment and after the end of therapy. The decline in hemoglobin (Hb) or platelet (PLT) level at week 4 compared to baseline was also assessed according to ribavirin concentrations.ResultsPatients with theITPA-CA/AAgenotypes showed a lower degree of Hb reduction throughout therapy than those with theITPA-CCgenotype and a marked difference in mean Hb reduction was found at week 4 (CA/AA−1.0 vs.CC−2.8,p< 0.001). TheITPA-CCgenotype had significantly less reduction in the mean platelet count than theITPA-CA/AAgenotypes early during treatment (p< 0.001 for weeks 4 and 8). Patients with theITPA-CA/AAgenotypes were less likely to develop anemia, regardless of the concentration of ribavirin. Patients with baseline PLT counts below 130 × 103/μl had a significantly lower tendency to achieve sustained virological response (SVR), especially those with theITPA-CA/AAgenotypes. ITPA gene variation was not extracted by multivariable analysis as an important predictor of SVR.ConclusionsDespite the fact that ITPA variants were less likely to develop anemia, patients with low baseline PLT counts were difficult to treat, especially those with theITPA-CA/AAgenotype. These results may give a valuable pharmacogenetic diagnostic tool for the tailoring of dosing to minimize drug-induced adverse events.