ITPA Gene Variant Protects Against Anemia Induced By Interferon-2α And Ribavirin Therapy

Background and objective:Hepatitis C is a kand of acute and chronic hepatic inflammation induced by the hepatitis C virus (HCV). In current,the global number of people infected with chronic hepatitis C is about 1.7 million and the prevalence of hepatitis C virus infection rate is about 2.2-3.0%.300 million to 400 million new cases will be found each year. In china,the anti-HCV positive rate was 3.2% and about 37 million to 40 million people infected with HCV. Interferon combined with ribavirin are the standard treatment for hepatitis C currently.With the progress of antiviral treatment withinterferon and ribavirin,we pay attention to the side effects of both drugs,among which the most serious side effect is the hemolytic anemia caused by ribavirin,of which 10-14% of patients need to reduce dose and withdraw treatment. Recently many researches showed that the gene variant of C20orf194(rs6051702 and rs1127354) and ITPA (rs7270101) correlated with the level of hemoglobin in chronic hepatitis C with treatment of pegylated interferon (Peg-INF) and ribavirin,which may be important in predicting the hemolytic anemia and adjusting the dose to increase the response rate during antiviral treatment.The pyrosequence was used to analyse the polymorphism of ITPA and C20orf194 in the population of northern in China in our stuy and to explore the relationship between the gene polymorphism and hemolytic anemia caused by ribavirin in chronic hepatitis C patients.The gene variant of the genes maybe the precictor of the hemolytic anemia and will provide a theoretical basis for the antiviral treatment.Methods: We determined C20orf194 (rs6051702) and ITPA (rs 1127354) single gene polymorphisms in 742 individuals with chronic hepatitis C,203 individuals with chronic HBV infection,203 individuals with self-limited HBV infection and 203 individuals negative for all HBV seromarkers.208 individuals with chronic hepatitis C were treated with interferon -2α(5×10 6IU subcutaneously every other day) and ribavirin(900mg every day).The routine blood test, liver function, HCV RNA quantification were examined at baseline,2 weeks,4 weeks and 12 weeks.Results:l.The variant of rs6051702 and rs1127354 are in line with Hardy Weinberg genetic equilibrium in the tested population.2.The correlation of the decrease of hemoglobin in 2 weeks,4 weeks and 12 weeks and the variant of ITPA(rs 1127354) were analyzed.The results showed that the hemoglobin were different between different genotypes.The hemoglobin level were lower in the AC and AA group with the minor allele A indicting the protective effect of A allele gene.3.The correlation of the decrease of hemoglobin in 2 weeks,4 weeks and 12 weeks and the variant of C20orf194(rs6051702) were analyzed.There was no difference between the hemoglobin level and the genotype.4. The decrease of hemoglobin level more than 3g/dl at 4 weeks in CC group were different from that of in AC and AA group(P=0.001).5. The linear regression analysis of the decrease of hemoglobin level were done at 2 weeks,4 weeks and 12 weeks.The results indicted that the decrease of hemoglobin level correlated with the hemoglobin level at baseline and with the variant of ITPA(rs1127354) at 2 weeks and 4 weeks.6. The variant of rs6051702 and rs1127354 are not in linkage disequilibrium.Conclusion: 1. No significant differences were observed in genotype and allele fre-quencies among these four study cohorts (203 individuals with chronic HBV infection,203 individuals with self-limitedHBV infection,203 individuals negative for all HBV seromarkers and 742 individuals with chronic hepatitis C).The distribution of genotype and allele frequencies were similar with individuals from Japan and Uuropean.2. There was no difference between the variant of C20orf194(rs6051702) and the hemoglobin level, the decrease more than 3g/dl of hemoglobin at 4 weeks, the severe anemia (Hb<10g/dl) in the Chinese northern patients with chronic hepatitis C during the treatment with interferon and ribavirin,which was different from the study aboard.3. Significant correlation was found between the variant of ITPA(rs1127 354) and the decrease of hemoglobin during the antiviral treatment,the decrease more than 3g/dl of hemoglobin at 4 weeks.The degree of anemia in the group with allele A (genotype AC and AA) were lower than that of the group with genotype CC,indicting the protective effect of allele A.So the variant of ITPA (rsl 127354) could be the predictor of anemia degree and induct the dose adju-stment of ribavirin.However,there was no correlation between the variant and the occurrence of severe anemia.4. The compliance of patients not only affect the treatment, but also affect the study results. So we should enhance the education and track the compliance of patients.