Clinical Advances in Liver, Pancreas, and Biliary TractITPA Polymorphism Affects Ribavirin-Induced Anemia and Outcomes of Therapy—A Genome-Wide Study of Japanese HCV Virus Patients
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Study Population
In this study, we adopted a 2-step genome-wide association study (GWAS) consisting of a screening phase (GWAS-1 and -2) and a subsequent replication analysis (Replication-1) using a total of 923 subjects. Samples of the GWAS-1 were genotyped in the context of another genome-wide study concerning the genetics of treatment response to HCV therapy. The demographic features of the subjects are shown in Table 1. All patients were infected with HCV genotype 1b and treated with PEG-IFN plus ribavirin
Genome-Wide Association Analysis and Replication Study
A total of 510,537 SNPs passed quality-control filters. During the quality-control check, 11 samples suggesting kinship or sample duplication were excluded from the analysis according to PI_HAT value. The threshold for genome-wide significant association was set at P < 9.8 × 10−8 (.05/510,537). The genomic distribution of SNP associations is shown in Supplementary Figure 1A. The quantile−quantile plot demonstrated that several SNPs showed a stronger association than would be expected by chance,
Discussion
The anemia experienced as a consequence of PEG-IFN and ribavirin combination therapy is primarily caused by a ribavirin-induced hemolysis and secondarily by an interferon-induced bone marrow toxicity. De Franceschi et al15 proposed that the mechanism of ribavirin toxicity is that ribavirin phosphate accumulation in erythrocytes mediates oxidative damage and cell lysis. It has been reported that anemia is the major reason for dose reduction.16 Various predictive factors for ribavirin-induced
Acknowledgments
The authors thank the patients who agreed to participate in this study. We also thank the team members at Toranomon Hospital, Hiroshima University Hospital, and Hiroshima Liver Study Group for clinical sample collection. We thank T. Yokogi, H. Ishino, and K. Izumoto, T. Takajyo, and J. Sakamiya for technical assistance; and other members of the RIKEN Center for Genomic Medicine and Hiroshima University for assistance with various aspects of this study.
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Conflicts of interest The authors disclose no conflicts.
Funding This study was supported in part by RIKEN and by Dainippon Sumitomo Pharma Co, Ltd.