IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis

Genetic variation in the IFNL3-IFNL4 (interferon-lambda 3-interferon-lambda 4) region is associated with hepatic inflammation and fibrosis1-4. Whether IFN-lambda 3 or IFN-lambda 4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-lambda 3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-lambda 4, but produces IFN-lambda 3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-lambda 4 protein and reduces IFN-lambda 4 activity, or between patients encoding functionally defective IFN-lambda 4 (IFN-lambda 4-Ser70) and those encoding fully active IFN-lambda 4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) 5,6 were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-lambda 3 rather than IFN-lambda 4 likely mediates IFNL3-IFNL4 haplotypedependent hepatic inflammation and fibrosis.