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

Background & Aims: 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.