Gastroenterology

Gastroenterology

Volume 139, Issue 4, October 2010, Pages 1190-1197.e3
Gastroenterology

Clinical Advances in Liver, Pancreas, and Biliary Tract
ITPA Polymorphism Affects Ribavirin-Induced Anemia and Outcomes of Therapy—A Genome-Wide Study of Japanese HCV Virus Patients

https://doi.org/10.1053/j.gastro.2010.06.071Get rights and content

Background & Aims

Ribavirin-induced anemia is one of the major causes of discontinuation and dose reduction during anti-hepatitis C virus therapy. Factors influencing this anemia, especially host genetic factors, are poorly understood. In this study we investigated predictive factors in hepatitis C virus patients treated with combination therapy.

Methods

We performed a 2-step genome-wide screening followed by replication analysis and fine-mapping using a total of 923 Japanese hepatitis C virus 1b−infected patients treated with pegylated-interferon plus ribavirin. We also applied logistic regression analysis to search for possible independent associations of clinical parameters and genetic variants with treatment-induced hemoglobin (Hb) decline as well as treatment outcomes.

Results

We identified a variant, located upstream of the inosine triphosphate pyrophosphatase gene on chromosome 20p13 that is significantly associated with treatment-induced anemia (combined P = 6.0 × 10−14). Resequencing and fine-mapping revealed several single nucleotide polymorphisms (SNPs) strongly associated with Hb decline, including the nonsynonymous SNP rs1127354 (P = 3.5 × 10−44), which was recently reported for other ethnic groups. Another reported SNP, the splicing variant-related SNP rs7270101, was not polymorphic in the Japanese population. Stratified analysis based on rs1127354 genotype revealed that inosine triphosphate pyrophosphatase expression is not correlated with Hb decline, suggesting that rs1127354 is a direct causal variant in the Japanese population. Multivariate analysis demonstrated that age, baseline Hb, baseline platelet count, and rs1127354 were independently associated with severe anemia (Hb <10 g/dL).

Conclusions

A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus−infected Japanese patients.

Section snippets

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.

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