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

Eslam, Mohammed; McLeod, Duncan; Kelaeng, Kebitsaone Simon; Mangia, Alessandra; Berg, Thomas; Thabet, Khaled; Irving, William L; Dore, Gregory J; Sheridan, David; Grønbæk, Henning; Abate, Maria Lorena; Hartmann, Rune; Bugianesi, Elisabetta; Spengler, Ulrich; Rojas, Angela; Booth, David R; Weltman, Martin; Mollison, Lindsay; Cheng, Wendy; Riordan, Stephen; Mahajan, Hema; Fischer, Janett; Nattermann, Jacob; Douglas, Mark W; Liddle, Christopher; Powell, Elizabeth; Romero-Gomez, Manuel; George, Jacob

Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 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-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.