title: Single and combined IL28B, ITPA and SLC28A3 host genetic markers modulating response to anti-hepatitis C therapy.
abstract: Advances in hepatitis C pharmacogenomics identified modulations of a sustained virologic response (SVR) by frequent IL28B gene variants and of ribavirin-induced hemolysis by frequent ITPA gene variants. These associations have been widely reproduced in various ethnicities, clinical settings and hepatitis C viral genotypes. The IL28B minor alleles rs8099917G, rs12979860T and rs12980275G have been associated with non-SVR whereas the ITPA minor alleles rs1127354A and rs7270101C were associated with less hemolytic side effects, an effect also attributed to a nucleoside transporter gene SLC28A3 rs10868138G/rs56350726T haplotype. The significance levels of these associations, especially in genome-wide studies, were very high. We nevertheless tested how good clinical outcomes of peginterferon α/ribavirin therapy, such as SVR or hemolytic side effects, were predicted by these variants. An analysis in an example dataset of 115 patients revealed that the prediction of non-SVR or hemolysis by single variants was often only slightly better than guessing. Using combinations of IL28B variants provided a higher accuracy (64.5%) of predicting non-SVR than with single IL28B variants (accuracy 60-63%). Similarly, a decline in blood hemoglobin by ≥3 g/dl could be better predicted at an accuracy of 70% (10% better than guessing) with a combination of an ITPA variant with a nucleoside transporter gene (SLC28A3) haplotype. Thus, genotyping information about single IL28B or ITPA variants is reproducibly and statistically significantly associated with hepatitis C therapy outcomes; however, the clinical predictive utility of single variants can be increased by combinations of genotypes.
authors: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital, Theodor Stern Kai 7, D-60590 Franfurt am Main, Germany. j.loetsch@em.uni-frankfurt.de
authors: Jörn
authors: J
authors: Lötsch
authors: Wolf Peter
authors: WP
authors: Hofmann
authors: Christina
authors: C
authors: Schlecker
authors: Stefan
authors: S
authors: Zeuzem
authors: Gerd
authors: G
authors: Geisslinger
authors: Alfred
authors: A
authors: Ultsch
authors: Alexandra
authors: A
authors: Doehring
mesh_terms: D000483:Alleles; D054316:Biomarkers, Pharmacological; D024921:Drug Resistance, Multiple, Viral; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006461:Hemolysis; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011755:Pyrophosphatases / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D000095022:Interferon Lambda; D000097630:Inosine Triphosphatase
chemical_list: D054316:Biomarkers, Pharmacological; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D026901:Membrane Transport Proteins; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C065171:cif nucleoside transporter; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C100416:peginterferon alfa-2a