Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399- 401. www.nature.com (Reprinted with permission.)
Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or-alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
Genomewide association studies (GWAS) examine genetic variation across a genome to identify associations that can be correlated with observable traits. GWAS are an example of personalized genomic medicine that promises the possibility of tailored therapy on the basis of individual genetic variability. These studies can be undertaken by a range of methods to identify genome loci in which a nucleotide base substitution, otherwise referred to as a single-nucleotide polymorphism (SNP), defines a genetic variation. However, the sheer complexity of the genome requires some assumptions in GWAS. The first is that not all known SNPs can be analyzed (currently there are in excess of 25 million SNP entries for humans in the National Center for Biotechnology Information database); second, the genome itself is predominantly composed of noncoding DNA (approximately 97%), meaning that many SNPs map to noncoding DNA sequences. Importantly, SNPs do not all occur at random and frequently associate, by linkage, with other SNPs in genomic loci (referred to as linkage disequilibrium). Therefore many GWAS identify SNPs thorough association and “map” or examine the genome at variable resolution of genomic detail. To date, few SNPs have been identified that directly influence disease treatment outcomes. Further, the association of SNPs identified with many diseases is often weak and of greater relevance on a population basis than to an individual.
Three landmark articles have now identified a SNP near the interleukin-28B (IL28B) gene that identifies a marked difference in treatment response to pegylated interferon in individuals with hepatitis C infection.1-3 A fourth article published at the same time describes an association of the same SNP with spontaneous clearance of hepatitis C virus (HCV).4 The IL28B gene encodes the protein interferon-λ3, which acts through the well-defined JAK-Stat (Janus kinase–signal transducer and activator of transcription) pathway leading to the induction of hundreds of interferon-stimulated genes (ISGs) that have already been widely implicated in both HCV treatment outcomes and spontaneous viral clearance (Fig. 1). The article by Ge and colleagues analyzed the IDEAL study cohort of 1137 patients and demonstrated that the IL28B polymorphism was a stronger predictor of HCV treatment outcome (odds ratio [OR] = 7.1) than either baseline viral load (OR = 4.2) or fibrosis grade (OR = 3.0).3 At the same time, an article by Suppiah et al. identified a IL28B gene polymorphism in an Australian cohort that was associated with a weaker effect on interferon-alpha (IFN-α) responsiveness (OR = 2.0).1 A further supporting manuscript by Tanaka et al. identified another IL28B gene SNP in a Japanese population, which associates by linkage disequilibrium with the SNPs identified in the other two manuscripts.2 In this case, the effect on interferon responsiveness was even more profound (OR = 17.7).2 Clearly, the association of IL28B gene polymorphisms with HCV treatment responses is strong, although there are many cofactors, including population genetics, that influence this association.
A final pivotal article from the same group as Ge et al. demonstrates that this IL28B polymorphism influences HCV spontaneous clearance.4 Those individuals with the favorable genotype were three times more likely to clear HCV infection.4 Importantly, this article demonstrated marked variation in the frequency of this genetic variant in different populations. Therefore, we can conclude that HCV treatment responses and spontaneous viral clearance are influenced by variation in multiple genetic loci, one of the strongest of which is the demonstrated IL28B association. This polymorphism clearly has major implications for current HCV treatment practices, as well as raising a number of questions (Table 1): What is the effect of the polymorphism on IL28B? Does this polymorphism influence a noncoding regulatory element or, through a haplotype association, the coding region of the IL28B gene? Further, it is not known in which cells IL28B is expressed and how this influences clearance of HCV from infected hepatocytes.
|Current implications of identification of a favorable IL28B polymorphism|
|• Treat early in HCV liver disease|
|• Treatment of HCV genotype-1 liver disease for a shorter duration|
|• Avoidance of liver biopsy in HCV genotype-1 disease|
|Future questions raised by the IL28B polymorphisms|
|• What is the effect of the polymorphism on IL28B?|
|• Does this IL28B polymorphism influence a noncoding regulatory element or the coding region of IL28B?|
|• Which cells express IL28B?|
|• What is the associated beneficial interferon-stimulated gene profile?|
|• Do the associated treatment outcomes apply to non–genotype-1 disease?|
Finally, what does this tell us about the role of endogenous and exogenous interferons in HCV eradication? In general, the ISG effect on HCV replication is determined by variably induced ligand (endogenous IFN-α/-β, IFN-γ, IFN-λ1-3 and exogenous IFN-α2a/b) and receptor (IFNαR1/IFNαR2, IFNγR1/IFNγR2, or IFNλR1/IL10R2) expression and interactions (Fig. 1).5 Additionally, it is clear that there is an apparent paradoxical relationship between the level of endogenous ISG induction and the subsequent responsiveness of an HCV-infected individual to interferon therapy.6 Further, there are known differential effects of the many different ISGs on HCV replication.5, 7 This can lead us to assume that selective targeting the interferon pathways leading to a favorable ISG profile resulting in HCV eradication is possible. This is the basis behind new candidate therapeutics such as the Phase II trial of IL-29 (IFN-λ1) in HCV.7, 8
These four pivotal studies have simultaneously identified a significant predictor of HCV treatment response and at the same time provided new insight into HCV pathobiology. The findings may lead to personalized medicine in which the likelihood of an IFN-α2a/2b treatment response can be determined prior to treatment. However, even greater promise may be realized by the development of newer therapeutic agents that more selectively target antiviral responses in HCV infection.