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中华实验和临床感染病杂志(电子版)

中华实验和临床感染病杂志(电子版) ›› 2017, Vol. 11 ›› Issue (02) : 168 -171. doi: 10.3877/cma.j.issn.1674-1358.2017.02.013

临床论著

广州地区丙型肝炎患者肌苷三磷酸酶基因多态性与利巴韦林所致贫血的相关性
邓浩辉1, 许敏1, 李晓强1, 雷春亮1,†()   
  1. 1. 510060　广州市，广东省广州市第八人民医院肝病科
  • 收稿日期:2016-02-27 出版日期:2017-04-15
  • 通信作者: 雷春亮
  • 基金资助:
    广州市医药卫生科技项目(No. 20141A010033)

Correlation of inosine triphosphate pyrophosphatase single nucleotide polymorphism and ribavirin-related anemia in patients with chronic hepatitis C in Guangzhou

Haohui Deng1, Min Xu1, Xiaoqiang Li1, Chunliang Lei1,†()   

  1. 1. Department of Liver Diseases, Guangzhou the Eighth People’s Hospital, Guangzhou 510060, China
  • Received:2016-02-27 Published:2017-04-15
  • Corresponding author: Chunliang Lei
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邓浩辉, 许敏, 李晓强, 雷春亮. 广州地区丙型肝炎患者肌苷三磷酸酶基因多态性与利巴韦林所致贫血的相关性[J]. 中华实验和临床感染病杂志(电子版), 2017, 11(02): 168-171.

Haohui Deng, Min Xu, Xiaoqiang Li, Chunliang Lei. Correlation of inosine triphosphate pyrophosphatase single nucleotide polymorphism and ribavirin-related anemia in patients with chronic hepatitis C in Guangzhou[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2017, 11(02): 168-171.

目的

探讨慢性丙型肝炎患者肌苷三磷酸（ITPA）单核苷酸基因多态性（SNP）与治疗过程中利巴韦林相关溶血性贫血发生的相关性。

方法

收集本院2012年3月至2015年9月收治的使用聚乙二醇化干扰素（PegIFN）联合利巴韦林抗病毒治疗的慢性丙型肝炎患者的全血标本，采用直接测序法检测ITPA rs1127354、rs7270101和20号染色体连锁的rs6051702位点的SNP，并收集患者抗病毒治疗后第4、12、24、36、48周血红蛋白（Hb）数据和药物调整情况，使用独立样本t检验、卡方检验、重复测量和多变量方差分析比较不同位点SNP和利巴韦林相关贫血、药物调整的关系。

结果

本研究共纳入85例丙型肝炎患者，其中78例患者完成48周抗病毒治疗并有完整的随访资料。85例患者中ITPA rs1127354位点CC型61例（71.8%），AC型21例（24.7%），AA型3例（3.5%）；rs7270101位点85例均为AA型（100%）；20号染色体rs6051702位点CC型2例（2.3%），AC型22例（25.9%），AA型61例（71.8%），其中7例未完成治疗的患者rs1127354位点均为CC型，rs6051702位点均为AA型。完成48周抗病毒治疗的78例患者中，rs1127354位点AC和AA型有4例（16.7%）患者在治疗过程中需调整利巴韦林剂量，24例（44.4%）CC型患者需调整利巴韦林剂量，差异有统计学意义（χ2 = 5.571、P = 0.018）；rs6051702位点的SNP与药物剂量调整无显著相关性（χ2 = 1.789、P = 0.182）。rs1127354位点AC型和AA型患者治疗第4周、12周、24周血红蛋白下降水平显著低于CC型患者（P均< 0.05）。

结论

广州地区ITPA rs7270101位点不存在SNP，rs1127354位点AA型和AC型对利巴韦林相关贫血有保护作用，对该位点SNP检测有利于指导临床医生个体化用药。

关键词: 肝炎, 丙型, 慢性, 肌苷三磷酸酶, 利巴韦林, 贫血
Objective

To investigate inosine triphosphate pyrophosphatase (ITPA) single nucleotide polymorphism (SNP) in patients with hepatitis C in Guangzhou and the correlation of ribavirin-related anemia during 48 weeks antiviral therapy.

Methods

The blood sample of hepatitis C patients treated with polyethylene glycol interferon (PegIFN) and ribavirin (RBV) were collected to detect SNP of ITPA rs1127354, rs7270101 and rs6051702 on chromosome 20 by direct sequencing method, and the data of hemoglobin (Hb) at 4, 12, 24, 36 and 48 weeks during treatment were collected and analyzed by independent-samples t test, χ2 test, repeated measures and multivariate ANOVA.

Results

Total of 85 patients with hepatitis C were enrolled, including 78 patients with hepatitis C who finished the 48 weeks treatment. Among the 85 patients with hepatitis C, genotyping of ITPA rs1127354 showed that 3 patients (3.5%) were homozygous for AA, 21 patients (24.7%) were heterozygous for AC, 61 patients (71.8%) were homozygous for CC. All the 85 patients were homozygous for AA in ITPA rs7270101. Two patients (2.3%) in rs6051702 on chromosome 20 were homozygous for CC, 22 patients (25.9%) were heterozygous for AC, 61 patients (71.8%) were homozygous for CC. Four patients (16.7%) in rs1127354 AA and AC needed to reduce the dose of ribavirin during the treatmet, however, the chance of reducing the dose of ribavirin was much higher in rs1127354 CC genotype (χ2 = 5.571, P = 0.018), and rs6051702 genotypes were not significantly related to dose reduction of ribavirin (χ2 = 1.789, P = 0.182). Anemia in rs1127354 CC genotype was more frequent than AA and AC genotypes at 4, 12 and 24 weeks during treatment (P all < 0.05).

Conclusions

ITPA rs7270101 SNP doesn’t among hepatitis C patients in Guangzhou. The rs1127354 AC/AA genotypes were protective factor for ribavirin related anemia.

Key words: Hepatitis C, Inosine triphosphate pyrophosphatase, Ribavirin, Anemia
表1 ITPA和20号染色体连锁的SNP位点的引物序列
SNP位点 上游引物（F） 下游引物（R）
rs1127354 5'-AAGAGATAGAGAAGCAAGGA-3' 5'-CTGGACAAGAAGAGCAAGT-3'
rs7270101 5'-GAAGAGATAGAGAAGCAAGGA-3' 5'-CTGGACAAGAAGAGCAAGT-3'
rs6051702 5'-GGTATCTAGCTGATACTTGG-3' 5'-CCTGTGAATTTTACTTCTGT-3'
表2 85例丙型肝炎患者ITPA rs1127354、rs7270101和20号染色体连锁rs6051702位点的基因多态性[例（%）]
SNP位点 CC型 AC型 AA型 Hardy-Weinberg检验（χ2值） P值
rs1127354 61（71.8） 21（24.7） 3（3.5） 0.4828 0.4871
rs6051702 2（2.3） 22（25.9） 61（71.8） 0.0001 0.9921
rs7270101 0（0.0） 0（0.0） 85（100.0） — —
表3 78例患者48周治疗过程中rs1127354和rs6051702位点各时间点血红蛋白下降水平（±s，g/dl）
治疗时间 rs1127354 rs6051702
CC型（n = 54） AC/AA型（n = 24） F值 P值 AA型（n = 54） AC/CC型（n = 24） F值 P值
4周 1.81±1.60 0.56±1.02 11.401 0.001 1.56±1.80 1.45±1.19 0.047 0.830
12周 3.30±1.68 2.43±1.41 4.395 0.040 3.21±1.68 2.79±1.81 0.674 0.415
24周 3.68±1.75 2.76±1.54 4.459 0.038 3.67±1.70 2.72±2.06 3.136 0.082
36周 3.38±1.87 3.14±1.96 0.241 0.625 3.27±1.67 4.53±4.24 2.612 0.112
48周 1.68±2.24 2.58±2.20 2.423 0.124 2.67±2.97 2.76±3.40 0.008 0.930
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