A Polymorphism in MAPKAPK3 Affects Response to Interferon Therapy for Chronic Hepatitis C

Background & Aims

This study aimed to identify host single nucleotide polymorphisms (SNPs) that are associated with the efficacy of interferon (IFN) therapy in patients with chronic hepatitis C.

Methods

We examined whether 116 tagging-SNPs from 13 genes that are involved in type I IFN signaling associate with the outcome of IFN therapy in Japanese case-control groups; the study included 468 sustained responders and 587 nonresponders.

Results

We identified 2 SNPs (rs3792323 [A/T] and rs616589 [G/A]), located in intron 2 of mitogen-activated protein kinase–activated protein kinase 3 (MAPKAPK3) that were associated with the outcome of IFN therapy in patients infected with hepatitis C virus (HCV) genotype 1b (P = 4.6 × 10⁻⁵ and 4.8 × 10⁻⁵, respectively). The 2 SNPs were in strong linkage disequilibrium and multivariate logistic regression analysis showed that rs3792323 is an independent factor associated with the IFN efficacy (genotype 1b; P = .0011). MAPKAPK3 is a kinase involved in the mitogen and stress responses, but the biological significance of MAPKAPK3 in IFN responses is poorly understood. By using an allele-specific transcript quantification assay in liver biopsy, we showed that allele-specific expression of MAPKAPK3 messenger RNA, corresponding to the risk allele for nonresponse, was significantly higher than that of the other allele. Luciferase reporter assay data indicated that overexpression of MAPKAPK3 inhibits IFN-alfa–induced gene transcription via IFN-stimulated response element and IFN-γ–activated site.

Conclusions

The SNP rs3792323 in MAPKAPK3 associates with the outcome of IFN therapy in patients with HCV genotype 1b. Our functional analyses indicate that MAPKAPK3 inhibits IFN-alfa–induced antiviral activity.

Abbreviations used in this paper: GAS, interferon-γ–activated site, IFN, interferon, IFNAR1, type I interferon receptor-1, ISRE, interferon-stimulated response element, JAK, Janus-activated kinase, MAP, mitogen-activated protein, MAPKAPK, mitogen-activated protein kinase–activated protein kinase, MAPKK, mitogen-activated protein kinase kinases, NR, nonresponders, SNPs, single nucleotide polymorphisms, SR, sustained responders, STAT, signal transducer and activator of transcription