Predictors of Response in Hepatitis C Virus Disease Therapy
performed a GWAS in approximately 1,700 patients from the Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study and from another prospective treatment trial. In summary, the IDEAL trial showed regimens of PEG-IFN-α-2a/RBV and PEG-IFN-α-2b/RBV to have similar efficacy. Patients included in the GWAS analysis were of European-American, African-American or Hispanic ancestry. Based on analysis of the genomes of 1,137 adherent patients with HCV infection, Ge et al. identified seven separate single nucleotide polymorphisms (SNPs) near the interleukin 28B gene (IL28B; encoding IL-28B, also known as IFN-lambda-3) on chromosome 19 that were significantly more common in responders than non-responders. The association with SVR of the top discovery of the SNP rs12979860, which is located 3kb upstream of IL28B, was of overwhelming genome-wide significance (p=1.37x10-28). A total of six other SNPs in the same gene region, including rs8099917, were significantly associated with SVR; they displayed different degrees of linkage disequilibrium with rs12979860 and their effects were largely explained by rs12979860. The ‘good response’ CC genotype of rs12979860 was associated with a more than two-fold greater rate of SVR (depending on ethnicity) compared with the TT genotype. Furthermore, the good response C allele was much more frequent in individuals of European ancestry than it was in African-Americans. These differences in the good response C allele and CC genotype frequencies explained approximately half of the difference in SVR rates that were observed between the patients of European versus African ancestry.
Host Genetic Variation and Treatment Response Ge et al.23
Two other independent GWAS in patients with HCV genotype 1 infection support the data from the analysis by Ge and colleagues. Suppiah et al.24
the causal variant remains unclear. In this context, both SNPs appear to possess similar potential clinical utility for identifying good responders to standard-of-care HCV therapy, except in patients of African ancestry, in whom rs12979860 is more strongly associated with treatment outcome. It is important to note that the genotyping chips in the Suppiah and Tanaka studies did not include rs12979860.
Host Genetic Variants and Spontaneous Clearance
The results of the Ge et al. analysis also pointed towards the good response C allele of rs12979860 favouring spontaneous HCV clearance. This allele was more frequent in an ethnically matched non-HCV-infected multiethnic population versus an ethnically matched, chronically infected study cohort (0.63 versus 0.73, respectively; controlled for population structure; p
They genotyped the
rs12979860 SNP in 1,008 patients from six independent HCV cohorts composed of individuals who either spontaneously cleared the virus (n=388) or else had persistent infection (n=620). The frequency of the good response C allele was higher in the clearance group versus the persistence group in individuals of European ancestry (80.3 versus 66.7%, respectively; p=7x10-8) and in those of African-American ancestry (56.2 versus 37%, respectively; p=1x10-5). It was also noted that patients with the good response CC genotype were much more likely to achieve HCV clearance than those having the CT and TT genotypes combined (p
carried out a GWAS in 293 Australian patients of northern European ancestry, which was followed by a validation step in an independent replication cohort of 555 Europeans from the UK, Germany, Italy and Australia. They identified the rs8099917 SNP (located ~8kb upstream of IL28B) that was significantly associated with SVR (p=9.39x10-9). Numerous other SNPs near IL28B were also identified that had suggestive levels of association with SVR (p
carried out a similar two-stage GWAS in Japanese patients. They investigated null virological response (NVR) at week 12 of therapy as well as SVR in the treatment of patients with HCV genotype 1 infection. The researchers identified two SNPs near IL28B on chromosome 19 that were strongly linked to NVR (rs12980275, p=2.84x10-27; rs8099917, p=2.68x10-32). These SNPs were also strongly associated with SVR (rs12980275, p=3.99x10-24; rs8099917, p=1.11x10-27), with the strongest association reported for rs8099917. The researchers also identified several other SNPs present in the IL28B region that were associated with SVR.
Tanaka et al.25
It should be noted that current GWAS genotyping chips take advantage of linkage disequilibrium patterns and ‘tag’ SNPs (identified by the HapMap project) to cover in excess of 90% of common genetic variants. The tag SNPs identify a locus of the genome (i.e. a haplotype block) that is associated with a trait of interest, in this case HCV treatment response. In most cases, they do not represent the causal variant itself. rs12979860 and rs8099917 are two tag SNPs that point to the same haplotype block. As yet,
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
Association of Host Genetic Variants with the Expression of the Interleukin 28B Gene In the GWAS by Tanaka et al.,25
a realtime polymerase chain reaction
(RT-PCR) assay was carried out in peripheral blood mononuclear cells (PBMCs) to test the expression of IL28B in a small cohort of 20 HCV patients. Among this cohort, 10 patients had the advantageous allele whereas the other 10 did not. The results of this assay showed a weak signal for lower expression of IL28B in patients with the risk (i.e. ‘poor response’) allele of rs8099917 (p=0.015), suggesting that the variant(s) regulate IL28B expression. Also, Suppiah et al.24
found
a weak signal for lower expression of IL28A and IL28B in PBMCs from healthy individuals with the poor-response haplotype of rs8099917 (p=0.044). However, in the Ge et al.23
study there was no
signal detected for differences in the expression of IL28B in PBMCs from healthy individuals with either the good response or poor response rs12979860 genotypes. Therefore, the currently available evidence is conflicting and based on small numbers of HCV patients/healthy controls.
Further studies are necessary to explore the relationship between the IL28B genotype and IL28B expression in peripheral cells and, more importantly, in liver tissue from HCV-infected individuals. Alternatively, it may be that these SNPs are associated with the function of IL28B and, thereby, the degree of viral control. For instance, the Ge et al. study reported the rs12979860 SNP to be in strong linkage disequilibrium (r2.0.85) with a non-synonymous coding variant in IL28B (213A.G, K70R; rs8103142).23
The mechanism 67
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