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RESEARCH PRODUCT

Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease

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Background and Aims: The IFNL3/4 locus influencing innate immunity regulation has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in NAFLD. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of NASH. To clarify the mechanism, we also evaluated the impact on interferon-stimulated gene (ISG) hepatic expression in a subset of patients. Methods: We considered 946 consecutive Italian individuals at risk of NASH with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and PNPLA3 rs738409 C>G polymorphisms were genotyped and ISG hepatic expression (n=16) tested by TaqMan assays. Results: We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (OR 1.53, 95% CI 1.15-2.31; P=0.005), as well as with severe (grade 2-3) lobular necroinflammation (OR 1.47, 95% CI 1.14-1.88; P=0.002). The impact of rs368234815 on liver damage was generally more marked in non-obese individuals, where association with severe fibrosis, necroinflammation and also NASH was observed (p<0.05). ISG were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (p<0.05). Similar results were observed when considering rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2=0.87). Conclusions: The IFNL4 genotype is associated with severity of fibrosis in NAFLD patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. This article is protected by copyright. All rights reserved.