慢性丙型肝炎患者干扰素治疗相关性血细胞减少的全基因组关联研究

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作者: 迟秀梅发布日期: 2012-03-30 阅读次数：

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背景：干扰素-α（IFN）相关的血细胞减少症较为常见，并可能受剂量影响。我们对一组确定为基因型1丙型肝炎感染的研究队列进行了基因组关联研究，寻找聚乙二醇干扰素（peg-IFN）相关的血小板减少症，中性粒细胞减少症和白细胞减少减少症的遗传因素。方法：参加IDEAL研究（共 3070名）中1604名患者进行遗传学检测。试验入选标准包括：血小板计数≥80×10⁹ / L，中性粒细胞绝对值（ANC）≥1500/mm³。样品基因信息检测使用Illumina Human610磁珠芯片。主要分析第4周时依从性超过80%的患者的遗传因素对细胞计数（血小板，中性粒细胞绝对值，淋巴细胞，单核细胞，嗜酸性粒细胞，嗜碱性粒细胞）的影响（n = 1294）。结果：20号染色体上有6个SNPs位点与血小板减少是正相关（最明显的位点是SNP rs965469，P = 10^-10）。这些标签SNPs与ITPA基因的2个功能位点rs1127354和rs7270101，是连锁不平衡，这些变异位点造成ITP酶缺乏并能防止利巴韦林引起溶血性贫血（HA）。rs1127354和rs7270101 位点与血小板减少有很强的独立相关性（P = 10^-12，P = 10^-7），并能完全解释全基因组的显着关联性。我们相信这是由于利巴韦林引起贫血的血小板反应间接遗传相关性的一个例子：血红蛋白下降与血小板减少呈负相关（r = -0.28，P = 10^-17），回归模型中血红蛋白的变化很大程度上削减了ITPA变异与血小板减少的相关性。常见的遗传变异和pegIFN引起的中性粒细胞减少症或白细胞减少症没有相关性。结论：ITPA两个变异位点与血小板减少症有相关性，这在很大程度上解释了利巴韦林产生的溶血性贫血削减了干扰素产生的血小板减少症。pegIFN诱导的中性粒细胞减少症暂时无遗传因素被确认。

吉林大学第一医院肝胆胰内科迟秀梅摘译

本文首次发表于[Hepatology, 2012, 56: 313–319]

Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients

Background & Aims:

Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-a (peg-IFN)-related thrombocytopenia, neutropenia, and leukopenia.

Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count≥80×10⁹/L and an absolute neutrophil count (ANC)≥1500/mm³. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts(Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n = 1294).

Results:

6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p = 10^-10).These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10^-12, p=10^-7) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r = -0.28,p = 10^-17) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.

Conclusions:

Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

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