These authors contributed equally to the study.
Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus
Article first published online: 5 JAN 2015
© 2014 by the American Association for the Study of Liver Diseases
Volume 61, Issue 2, pages 460–470, February 2015
How to Cite
Hoffmann, F. S., Schmidt, A., Dittmann Chevillotte, M., Wisskirchen, C., Hellmuth, J., Willms, S., Gilmore, R. H., Glas, J., Folwaczny, M., Müller, T., Berg, T., Spengler, U., Fitzmaurice, K., Kelleher, D., Reisch, N., Rice, C. M., Endres, S. and Rothenfusser, S. (2015), Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus. Hepatology, 61: 460–470. doi: 10.1002/hep.27344
Potential conflict of interest: Dr. Hoffmann received grants from Novartis.
Supported by DFG RO 2525/3-1, Schm 2670/1-1 and RO 2525/5-1 to S.R., DFG GK 1202 to A.S., S.E. and S.R., by LMUexcellent (CIPSM 114, research professorship) and BayImmuNet to S.E., by National Institutes of Health grant AI091707 to C.M.R., and by a Rockefeller University Women and Science grant to M.D.C. T. Berg is supported by the German Competence Network for Viral Hepatitis (Hep-Net) through BMBF Grant No. 01 KI 0437, by the EU-Vigilance network of excellence combating viral resistance (VIRGIL, Project No. LSHM-CT-2004-503359) and by BMBF Grant No. 01KI0787.
See Editorial on Page 418
- Issue published online: 20 JAN 2015
- Article first published online: 5 JAN 2015
- Accepted manuscript online: 30 JUL 2014 04:14AM EST
- Manuscript Accepted: 28 JUL 2014
- Manuscript Received: 4 DEC 2013
Among patients newly infected with hepatitis C virus (HCV), only 20-30% clear the infection spontaneously. In the remaining 70% the infection persists, causing chronic liver inflammation and disease. It is well established that polymorphisms in host genes, especially in components of the innate immune response, contribute to the phenomenon of spontaneous HCV clearance. Retinoic acid inducible gene-I (RIG-I)-like helicases such as melanoma differentiation-associated gene 5 (MDA-5) are cytoplasmic sensors of viral RNA that are critical for triggering innate immune responses after infection with RNA viruses. We analyzed 14 nonsynonymous single-nucleotide polymorphisms in RIG-I-like helicase-pathway-genes comparing European patients who spontaneously cleared HCV (n = 285) or had persistent infection (n = 509). We found that polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine at position 946 strongly correlate with the resolution of HCV infection (odds ratio [OR]: 16.23; 95% confidence interval [CI]: 3.67-71.87; P = 1.1 × 10−6). Overexpression of MDA-5 genetic variants in HEK 293 cells and in a tissue culture model of HCV infection revealed that the histidine 843/threonine 946 variant leads to increased baseline and ligand-induced expression of interferon-induced genes and confers an increased ability to suppress HCV replication. Conclusion: These data suggest that MDA-5 plays a significant role in the defense against HCV and that polymorphisms in MDA-5 can influence the outcome of HCV infection. (Hepatology 2015;61:460-470)