title: Association of polymorphisms in the promoter regions of TNF-α (-308) with susceptibility to hepatitis E virus and TNF-α (-1031) and IFN-γ (+874) genes with clinical outcome of hepatitis E infection in India.
abstract: OBJECTIVE
  Hepatitis E virus (HEV) is the predominant cause of acute viral hepatitis (AVH-E) and acute liver failure (ALF-E) among adults from developing countries. Pathogenesis of hepatitis E is poorly understood. Earlier, we showed association of elevated serum levels of TNF-α, IFN-γ, and IL-12 with ALF-E. The role of TNF-α and IFN-γ gene promoter polymorphisms with disease severity was investigated.
  
  
  METHODS
  The study population included 374 anti-HEV negative apparently healthy controls, 136 subclinical hepatitis E, 353 AVH-E, and 25 ALF-E patients. Polymorphisms at promoter regions of TNF-α-308G/A, TNF-α-1031T/C, and IFN-γ+874T/A were investigated employing allelic discrimination/SNaPshot™ methods.
  
  
  RESULTS
  ALF-E patients were younger with significantly higher ALT levels when compared to other categories. Genotype TNF-α-308AA frequency was significantly higher among subclinical and clinical hepatitis E than the controls (p=0.03, 0.0007). No significant difference was observed among AVH-E/ALF-E groups. The -308A allele was significantly higher in HEV-infected individuals; fatal ALF patients showed higher frequency than the recovered (p=0.024). TNF-α-1031CC, IFN-γ+874TT, and IFN-γ+874TA genotypes were significantly associated with clinical disease. With respect to the controls, genotype+874TA was more frequent in subclinical infection (p=0.005) while+874AA frequency was lower in the AVH-E category (p=0.003).
  
  
  CONCLUSIONS
  The data reveal association of TNF-α-308AA genotype with susceptibility to HEV and that of TNF-α-1031CC and IFN-γ+874TT and TA with clinical disease, irrespective of the outcome. Higher -308A allele frequency was associated with susceptibility to HEV and the fatal outcome of ALF-E.
authors.affiliation: Hepatitis Group, National Institute of Virology, Pune, India.
authors.forename: Nischay
authors.initials: N
authors.lastname: Mishra
authors.forename: Vidya A
authors.initials: VA
authors.lastname: Arankalle
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D016751:Hepatitis E / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007194:India; D007371:Interferon-gamma / Q000235:genetics*; D017114:Liver Failure, Acute / Q000209:etiology / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
chemical_list: D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma