ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C

Naoya Sakamoto; Yasuhito Tanaka; Mina Nakagawa; Hiroshi Yatsuhashi; Shuhei Nishiguchi; Nobuyuki Enomoto; Seishin Azuma; Yuki Nishimura-Sakurai; Sei Kakinuma; Nao Nishida; Katsushi Tokunaga; Masao Honda; Kiyoaki Ito; Masashi Mizokami; Mamoru Watanabe

doi:10.1111/j.1872-034X.2010.00741.x

ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C

Hepatol Res. 2010 Nov;40(11):1063-71. doi: 10.1111/j.1872-034X.2010.00741.x.

Authors

Naoya Sakamoto¹, Yasuhito Tanaka, Mina Nakagawa, Hiroshi Yatsuhashi, Shuhei Nishiguchi, Nobuyuki Enomoto, Seishin Azuma, Yuki Nishimura-Sakurai, Sei Kakinuma, Nao Nishida, Katsushi Tokunaga, Masao Honda, Kiyoaki Ito, Masashi Mizokami, Mamoru Watanabe

Affiliation

¹ Department of Gastroenterology and Hepatology Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan.

PMID: 20977565
DOI: 10.1111/j.1872-034X.2010.00741.x

Abstract

Aim: Host genetic variants leading to inosine triphosphatase (ITPA) deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in chronic hepatitis C patients receiving ribavirin. In this study, we evaluated the clinical significance of ITPA variants in Japanese hepatitis C patients who were treated with pegylated interferon plus ribavirin.

Methods: In this multicenter retrospective cross-sectional study, 474 hepatitis C patients were enrolled who were treated with pegylated interferon plus ribavirin in four geographically different hospitals in Japan. Patients were grouped according to hemoglobin decline of more than 3 g/dL at week 4. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs6051702, rs1127354) were genotyped.

Results: A functional SNP, rs1127354, within the ITPA exon was strongly associated with protection against anemia with only one (0.8%) in 129 patients with the ITPA minor variant A developing severe anemia (P=5.9×10(-20) ). For rs6051702, which had significant association in European-Americans, significant but weak association with severe hemoglobin reduction was found in Japanese (P= 0.009). In patients excluding genotype 1b and high viral load, those with the ITPA minor variant A achieved significantly higher sustained viral response rate than those with the major variant (CC) (96% vs 70%, respectively, P= 0.0066).

Conclusion: ITPA SNP, rs1127354, is confirmed to be a useful predictor of ribavirin-induced anemia in Japanese patients. Patients with the ITPA minor variant A (~ 27%) have an advantage in pegylated interferon plus ribavirin-based therapies, due to expected adherence of ribavirin doses, resulting in a higher viral clearance rate.