Erythropoietin rs1617640 G allele associates with an attenuated rise of serum erythropoietin and a marked decline of hemoglobin in hepatitis C patients undergoing antiviral therapy

Abstract

BackgroundA decline in hemoglobin (Hb) concentration during antiviral therapy in chronic hepatitis C (CHC) is a serious side effect. It may compel to dose reduction or even termination of antiviral treatment. The activation of erythropoietin (EPO) synthesis as a physiological response to anemia and its relation to a genetic variation within the EPO gene has not been evaluated yet.MethodsData of 348 CHC patients were reviewed retrospectively. Samples were genotyped for EPO rs1617640 and inosine triphosphatase (ITPA) rs1127354. Serum EPO concentrations were determined before and during therapy. Primary endpoints were set as Hb decline >3 g/dl at weeks 4 and 12.ResultsEPO rs1617640 G homozygotes showed a significantly lower rise of serum EPO level over time than T allele carriers (p < 0.001). The cumulative frequency of a significant Hb reduction added up to 40%. Multivariate analysis revealed that besides age, ribavirin starting dose and baseline Hb also EPO rs1617640 G homozygosity associates with Hb reduction at week 4 (p = 0.025) and 12 (p = 0.029), while ITPA C homozygotes are at risk for Hb decline particularly early during treatment. Furthermore, EPO rs1617640 G homozygotes were more frequently in need for blood transfusion, epoetin-α supplementation, or ribavirin dose reduction (p < 0.001).ConclusionsOur data suggest that EPO rs1617640 genotype, the rise of serum EPO concentration as well as ITPA rs1127354 genotype are promising parameters to evaluate the Hb decline during antiviral therapy. A rational adjustment of therapy with epoetin-α supplementation might prevent serious adverse events or the need to terminate treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-503) contains supplementary material, which is available to authorized users.

Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies

“…78 On the basis of our meta-analysis, each copy of the A-allele at rs1617640 was associated with 0.063 standard deviations (SD), equivalent to 0.32 IU/L, higher endogenous EPO levels (p ¼ 9.32 3 10 À4 ) (Table 1). The effect of the cis-EPO variant is consistent with that previously reported in affected individuals with diabetic retinopathy or hepatitis C. 78,79 The cis-EPO SNP is associated with altered EPO expression and nearby TFR2 expression in the liver To provide additional insight into the rs1617640-EPO association and further evaluate its utility as an instrument, we tested the association of the cis-EPO SNP with gene expression in the kidney and the liver as EPO is highly expressed in these two tissues. 80 In the liver, we found that the C allele at rs1617640 was associated with higher EPO expression (b ¼ 0.22 [0.14, 0.3], p ¼ 6.86 3 10 À8 ) and also TFR2 expression (b ¼ 0.23 [0.17, 0.29], p ¼ 1.56 3 10 À13 ), a gene that lies upstream of the EPO gene and is involved in iron metabolism (Table S3).…”

“…Previous associations have been reported between variants near EPO and circulating EPO levels. 78,79 A cis-SNP, rs1617640, lying in the EPO promoter region, 1,125 bp upstream of the transcription start site, was associated with EPO levels in our study and in the previous study. 78 On the basis of our meta-analysis, each copy of the A-allele at rs1617640 was associated with 0.063 standard deviations (SD), equivalent to 0.32 IU/L, higher endogenous EPO levels (p ¼ 9.32 3 10 À4 ) (Table 1).…”

“…Our findings help clarify previous studies that found rs1617640 to have an allele-specific effect on EPO expression levels. Some had reported the A allele to be associated with higher EPO concentrations, 78,79 while others reported conflicting evidence with the C allele being associated with higher EPO concentrations and promoter activity. 83,84 We found an association between the variant and hepatic EPO gene expression; however, the C allele was found to be associated with increased hepatic EPO expression while the A allele was found to increase endogenous EPO levels (Table 1).…”

A prospective study on the changes of clinical values in HIV-Infected patients attending Kenyatta National Hospital Comprehensive Care Center

“…These two organs play a major role in erythropoiesis by producing hepcidin and erythropoietin respectively (Ganz and Nemeth, 2012;Amanzada et al, 2011;Beverborg et al, 2015). Inefficiencies of these organs will be key to anemia development.…”

Investigating the Association of rs1617640 Polymorphism in Patients with Diabetes Type II and Its Complications

“…rs1617640 G > T polymorphism in the EPO gene promoter increases EPO expression in mRNA and consequently protein level. Various studies investigated the association of this polymorphism with diabetes in different populations worldwide (1,(9)(10)(11). In this study we investigated the existence of rs1617640 EPO gene polymorphism among 150 healthy individuals and 150 individuals with diabetes type II who referred to Yazd (an Iranian province) central laboratory.…”