Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C

Abstract

The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

“…Genetic and functional studies have identified key molecules and processes involved in clearing HCV spontaneously and using interferon (IFN)‐α based therapies 3, 4, 5, 6, 7, 8, 9. These studies have implicated both innate and adaptive mechanisms in clearing HCV infection.…”

“…One of the most impressive findings from Gene Wide Association Studies (GWAS) to date has been the identification of single nuclear polymorphisms (SNPs) upstream of IFN‐λ3 which are protective against HCV chronicity and treatment failure 3, 4, 5, 6, 7. This has been fine mapped to the TT/‐G polymorphism at rs67272382 in a CpG island, which is in strong linkage disequilibrium with IFN‐λ3 and is most likely to be the causal variant, with the possibility of defining a new type 3 IFN, IFN‐λ4 10, 11.…”

Hepatitis C pharmacogenetics: State of the art in 2010

“…[3][4][5] The three genes encode IFN-k1 (IL29), IFN-k2 (IL28A), and IFN-k3 (IL28B). The same set of SNPs was subsequently associated with natural clearance of HCV.…”

IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity?

“…Genome-wide association studies have recently identified genetic variations near the IL28B gene, encoding for interferon (IFN)-k3, as a strong predictor of spontaneous and treatment-induced clearance of hepatitis C infection [13][14][15][16][17][18]. Protective variants at the rs12979860 and rs8099917 loci have consistently been associated with faster decline in viral load and an approximately twofold higher sustained virologic response rate during standard of care treatment, particularly, in patients affected by the difficult to cure HCV genotypes 1 and 4 [19,20].…”

“…Protective variants at the rs12979860 and rs8099917 loci have consistently been associated with faster decline in viral load and an approximately twofold higher sustained virologic response rate during standard of care treatment, particularly, in patients affected by the difficult to cure HCV genotypes 1 and 4 [19,20]. The mechanism by which these genetic variants influence the outcome of HCV infection, i.e., whether they influence IFN-k3 expression by affecting gene transcription or are linked to a coding variant (Lys70Arg) of the IFN-k3 protein, is still debated [14,18]. However, it is known that these variants result in a different pattern of activation of the innate immune system against HCV infection, as determined by the different basal and IFN-a induced expression of interferon-stimulated genes and inflammatory activity [21,22].…”