Impact of IL28B, ITPA and PNPLA3 genetic variants on therapeutic outcome and progression of hepatitis C virus infection

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Date: July 2015
From: Pharmacogenomics(Vol. 16, Issue 10)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 7,042 words
Lexile Measure: 2870L

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Author(s): Karolina Rembeck aff1 , Martin Lagging [*] aff1

Keywords:

genetic variant; HCV; histology; IL28B; inosine triphosphate pyrophosphatase; interferon-λ; ITPA; ITPase; natural history; PNPLA3; therapy

Hepatitis C virus (HCV)

The HCV was discovered in 1989, following an intensive search for the major etiologic agent associated with non-A, non-B hepatitis [1 ]. The HCV virus is a positive stranded RNA virus and belongs to the family of flaviviridae [2 ]. There are six major genotypes, and recently a seventh genotype was reported, all with different global geographic distributions [3-5 ]. If left untreated, HCV virus infection over time may progress to severe liver fibrosis, cirrhosis and hepatocellular carcinoma [6-8 ].

Interleukin 28B (IL28B ) genetic variants & impact on interferon-based HCV therapy

In 2009, a genome-wide association study (GWAS) demonstrated that several genetic variants in close proximity to the IL28B (also known as interferon-λ3) gene predicted greater likelihood of achieving a sustained virological response (SVR), in other words, undetectable HCV RNA 24 weeks after completion of therapy, following treatment with pegylated interferon-[alpha] (pegINF-[alpha]) and ribavirin among adherent HCV genotype 1 infected patients (Figure 1). The strongest association, among a predominantly Caucasian population, was noted for the single nucleotide polymorphism (SNP) rs12979860 where the CC variant had an almost two-fold increased likelihood of achieving SVR as compared with the TT variant [9 ]. The differences in C allele frequencies, with a greater frequency in Asian and European populations as compared with populations of African origin, could to a major extent explain the previously recognized racial differences in treatment response [9,10 ]. Furthermore the CC variant of rs12979860 also was associated with a greater first phase decline in HCV RNA (i.e., the reduction in HCV RNA during the first days of interferon therapy) as well as spontaneous clearance of the viral infection in HCV genotype 1, but somewhat counterintuitive, also with a higher baseline viral load [9,11,12 ].

Regarding patients infected with HCV genotype 2 or 3, the IL28B C allele also has been reported to be associated with greater first phase decline in HCV RNA as well as higher baseline viral load [12,13 ]. However, there is discordance regarding the potential benefit of the C allele regarding treatment outcome for these patients when treated with INF-[alpha] and ribavirin. Some studies have reported that CC variant of rs12979860, as compared with the TT variant, is associated with increased likelihood of achieving SVR among Caucasian patients [14,15 ], whereas others have failed to demonstrate such an association [ 13,16 ].

Another SNP, rs8099917, located in proximity to and in strong linkage disequilibrium (i.e., a nonrandom association of two alleles at two loci) with rs12979860 [12,17 ], also has been reported to be of significance regarding treatment outcome, especially among populations of Asian origin, where the CC variant of rs12979860 predominates. For HCV genotype 1 infected patients, the rs8099917 TT variant is associated with favorable treatment outcome, spontaneous virus clearance and greater first phase decline in HCV RNA, but also with a higher baseline viral load as compared with the TG and...

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Gale Document Number: GALE|A428534833