title: Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center of Integrated Protein Research Munich (CIPS-M) and Division of Clinical Pharmacology, Medizinische Klinik IV, University of Munich, Munich, Germany; Institute of Clinical Neuroimmunology, Klinikum Groβhadern, University of Munich, Munich, Germany.
authors.forename: Franziska S
authors.initials: FS
authors.lastname: Hoffmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmidt
authors.forename: Meike
authors.initials: M
authors.lastname: Dittmann Chevillotte
authors.forename: Christian
authors.initials: C
authors.lastname: Wisskirchen
authors.forename: Johannes
authors.initials: J
authors.lastname: Hellmuth
authors.forename: Simone
authors.initials: S
authors.lastname: Willms
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Gilmore
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.forename: Matthias
authors.initials: M
authors.lastname: Folwaczny
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Karen
authors.initials: K
authors.lastname: Fitzmaurice
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.forename: Nicole
authors.initials: N
authors.lastname: Reisch
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfusser
mesh_terms: D016022:Case-Control Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D016174:Hepacivirus / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000821:virology; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D011110:Polymorphism, Genetic; D012075:Remission, Spontaneous
chemical_list: C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1