%0 Journal Article
%A Eslam, Mohammed
%A McLeod, Duncan
%A Kelaeng, Kebitsaone Simon
%A Mangia, Alessandra
%A Berg, Thomas
%A Thabet, Khaled
%A Irving, William L
%A Dore, Gregory J
%A Sheridan, David
%A Grønbæk, Henning
%A Abate, Maria Lorena
%A Hartmann, Rune
%A Bugianesi, Elisabetta
%A Spengler, Ulrich
%A Rojas, Angela
%A Booth, David R
%A Weltman, Martin
%A Mollison, Lindsay
%A Cheng, Wendy
%A Riordan, Stephen
%A Mahajan, Hema
%A Fischer, Janett
%A Nattermann, Jacob
%A Douglas, Mark W
%A Liddle, Christopher
%A Powell, Elizabeth
%A Romero-Gomez, Manuel
%A George, Jacob
%A International Liver Disease Genetics Consortium (ILDGC)
%T IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis.
%D 2017
%U http://hdl.handle.net/10668/11076
%X 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.
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