Eslam, MohammedMcLeod, DuncanKelaeng, Kebitsaone SimonMangia, AlessandraBerg, ThomasThabet, KhaledIrving, William LDore, Gregory JSheridan, DavidGrønbæk, HenningAbate, Maria LorenaHartmann, RuneBugianesi, ElisabettaSpengler, UlrichRojas, AngelaBooth, David RWeltman, MartinMollison, LindsayCheng, WendyRiordan, StephenMahajan, HemaFischer, JanettNattermann, JacobDouglas, Mark WLiddle, ChristopherPowell, ElizabethRomero-Gomez, ManuelGeorge, JacobInternational Liver Disease Genetics Consortium (ILDGC)2023-01-252023-01-252017-04-10http://hdl.handle.net/10668/11076Genetic 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.enFibrosisGene FrequencyGenotypeHaplotypesHepacivirusHepatitis CHumansInflammationInterferonsInterleukinsLinkage DisequilibriumLiverLogistic ModelsMultivariate AnalysisPolymorphism, Single NucleotideReverse Transcriptase Polymerase Chain Reactionresearch article28394349open access10.1038/ng.38361546-1718https://iris.unito.it/bitstream/2318/1636123/1/Eslam%20M_NG2017.3836_Proof.pdf