Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C
Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C
复制标题
DOI：
10.1093/hmg/ddr249
复制
发表时间：
2011-09-01
影响因子：
3.5
通讯作者：
Mizokami, Masashi
中科院分区：
文献类型：
--
作者：
Tanaka, Yasuhito;Kurosaki, Masayuki;Mizokami, Masashi
目前使用聚乙二醇化干扰素和利巴韦林（PEG-IFN/RBV）治疗慢性丙型肝炎（CHC）时，血液学异常通常需要减少剂量和过早退出治疗。本研究的目的是通过全基因组关联研究（GWAS）确定与ifn诱导的血小板减少症相关的宿主因素。在GWAS阶段，使用900K单核苷酸多态性（SNP）微阵列对303名接受PEG-IFN/RBV治疗的日本CHC患者进行了基因分型。位于20号染色体上DDRGK1基因上的一个SNP （rs11697186）在次要等位基因-显性模型中与PEG-IFN/ rbv治疗后血小板计数减少有很强的相关性[P = 8.17 × 10(-9)；优势比(OR) = 4.6]。这些关联在另一个样本集（n = 391）中得到了重复，综合p值达到5.29 x 10(-17) （OR = 4.5）。与DDRGK1和ITPA基因周围的22个snp的精细定位表明，GWAS阶段的rs11697186与ITPA基因的功能变异rs1127354存在强烈的连锁不平衡。ITPA-AA/CA基因型与第4周血小板计数减少程度较高（P < 0.0001）以及对血红蛋白减少的保护作用独立相关，而与AA/CA基因型相比，CC基因型的平均血小板计数减少程度显著低于AA/CA基因型（第2、4、8、12周P < 0.0001），这是由于血小板计数在第1-4周反应性增加。我们目前的结果可能为定制PEG-IFN/RBV剂量以减少药物引起的不良事件提供有价值的药物遗传学诊断工具。
Hematologic abnormalities during current therapy with pegylated interferon and ribavirin (PEG-IFN/RBV) for chronic hepatitis C (CHC) often necessitate dose reduction and premature withdrawal from therapy. The aim of this study was to identify host factors associated with IFN-induced thrombocytopenia by genome-wide association study (GWAS). In the GWAS stage using 900K single-nucleotide polymorphism (SNP) microarrays, 303 Japanese CHC patients treated with PEG-IFN/RBV therapy were genotyped. One SNP (rs11697186) located on DDRGK1 gene on chromosome 20 showed strong associations in the minor-allele-dominant model with the decrease of platelet counts in response to PEG-IFN/RBVtherapy [P = 8.17 x 10(-9); odds ratio (OR) = 4.6]. These associations were replicated in another sample set (n = 391) and the combined P-values reached 5.29 x 10(-17) (OR = 4.5). Fine mapping with 22 SNPs around DDRGK1 and ITPA genes showed that rs11697186 at the GWAS stage had a strong linkage disequilibrium with rs1127354, known as a functional variant in the ITPA gene. The ITPA-AA/CA genotype was independently associated with a higher degree of reduction in platelet counts at week 4 (P < 0.0001), as well as protection against the reduction in hemoglobin, whereas the CC genotype had significantly less reduction in the mean platelet counts compared with the AA/CA genotype (P < 0.0001 for weeks 2, 4, 8, 12), due to a reactive increase of the platelet count through weeks 1-4. Our present results may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events.