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

Nature Genetics 49, 795 (2017). doi:10.1038/ng.3836 Authors: Mohammed Eslam, Duncan McLeod, Kebitsaone Simon Kelaeng, Alessandra Mangia, Thomas Berg, Khaled Thabet, William L Irving, Gregory J Dore, David Sheridan, Henning Grønbæk, Maria Lorena Abate, Rune Hartmann, Elisabetta Bugianesi, Ulrich Spengler, Angela Rojas, David R Booth, Martin Weltman, Lindsay Mollison, Wendy Cheng, Stephen Riordan, Hema Mahajan, Janett Fischer, Jacob Nattermann, Mark W Douglas, Christopher Liddle, Elizabeth Powell, Manuel Romero-Gomez & Jacob George 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 (r...
Source: Nature Genetics - Category: Genetics & Stem Cells Authors: Tags: Letter Source Type: research