Lost in translation? IL28B's discovery and the journey back to the patient

T he discovery that variation near the IL28B gene is strongly associated with treatment response to peginterferon and ribavirin (PEG/ RBV) for chronic hepatitis C virus (HCV) infection was significant in many respects. These studies were predicated on the hypothesis that a genetic factor may explain differences in sustained viral response (SVR), more specifically in the North American setting from the observation that African American patients had markedly lower SVR rates. These robust and wellvalidated findings were delivered via genome-wide association studies (GWAS) using high-coverage GWAS chips and assessing well-characterized patient cohorts. At first pass, this information suggested a means to improve prediction of response to poorly tolerated PEG/RBV regimens. Perhaps more broadly, it restored early faith that pharmacogenomics may resolve clinical uncertainties and deliver the promise of more personalized medicine. This faith had been rattled after an early history of idiosyncratic cohort-specific associations using candidate gene testing technology. Now, over 2 years on from the IL28B discovery, have these hopes been realized? What more do we know of the biology underlying this genetic association? Has information regarding IL28B transformed into knowledge that influences clinical understanding? Are there data to support clinical decision making? And importantly, is IL28B clinically relevant, as direct-acting antiviral (DAA)-inclusive regimens offer increasingly efficacious treatment for all patients? These issues are considered in a series of minireviews in this edition of HEPATOLOGY. The initial GWAS discoveries established association but not causation, which is very infrequently determined in GWAS. In fact, despite the widespread adoption of IL28B into the nomenclature, the IL28B gene remains only guilty by association, implicated by its proximity to the discovery variants and biological plausibility as a type III interferon (type III IFN, or IFN lambda I-III, including IL28A/B and IL29), rather than established functional linkage to a genetic variant. Urban and Goldstein consider the state of the basic science of IL28B, charting the genetic and biological progress, and the continuing substantial gaps in what we know. Perhaps the first of these basic gaps is the identification of the causal variant(s), or the genetic sequence(s), in which variation in code results either directly or indirectly in altered protein structure and/or function to explain the phenotype. The most promising putative functional variant to be studied to date has been rs8103142 (Lys70Arg missense variant); however, after exposure to a variant-determined recombinant IFN lambda, no difference in viral replication or gene expression was noted in a Huh 7.5 hepatocyte cell culture hosting a replicon model. Residual genetic associations with SVR remain after adjustment for IL28B, suggesting other loci may provide additional genetic contribution to variability in treatment response, and these remain to be determined. IL28B’s association has generated further interest in the biology of type III IFN and its potential as a therapeutic agent. Exploring associations with gene Abbreviations: DAA, direct-acting antiviral; GWAS, genome-wide association studies; HCV, hepatitis C virus; IFN, interferon; ISG, interferon stimulated gene; PEG, peginterferon; RAV, resistance-associated variant; RBV, ribavirin; RCT, randomized control trial; SVR, sustained viral response. Address reprint requests to: Andrew J. Muir, M.D., M.H. S. , Division of Gastroenterology, Duke University Medical Center 3913, 3140 Duke S Orange Zone, Durham, NC 27710. E-mail: muir0002@mc.duke. edu; fax: 919-684-8264. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25796 Potential conflict of interest: Nothing to report.