1. IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis
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Eslam, Mohammed, McLeod, Duncan, Kelaeng, Kebitsaone Simon, Mangia, Alessandra, Berg, Thomas, Thabet, Khaled, Irving, William, Dore, Gregory J., Sheridan, David, Grønbæk, Henning, Abate, María Lorena, Hartmann, Rune, Bugianesi, Elisabetta, Spengler, Ulrich, Rojas Álvarez-Ossorio, M. Ángeles, 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-Gómez, Manuel, George, Jacob, Metwally, Mayada, White, Rosa, Gallego-Durán, Rocío, Leung, Reynold, Mahajan, Neha, Bassendine, Margaret, Rahme, Antony, Rosso, Chiara, Mezzabotta, Lavinia, Malik, Barbara, Matthews, Gail, Asimakopoulos, Anastasia, Applegate, Tanya, Grebely, Jason, Fragomeli, Vicenzo, Jonsson, Julie R., Santoro, Rosanna, Sydney Medical Foundation, University of Sydney, and National Health and Medical Research Council (Australia)
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0301 basic medicine ,LAMBDA 4 ,Genotype ,health care facilities, manpower, and services ,education ,Inflammation ,Hepacivirus ,LIVER FIBROSIS ,GENOME-WIDE-ASSOCIATION ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,INTERFERON-STIMULATED GENES ,03 medical and health sciences ,Immune system ,Gene Frequency ,Fibrosis ,INFECTION ,Genetics ,medicine ,Humans ,HCV CLEARANCE ,SNP ,C VIRUS ,health care economics and organizations ,Hepatitis ,Reverse Transcriptase Polymerase Chain Reaction ,Interleukins ,Haplotype ,medicine.disease ,Hepatitis C ,Phenotype ,III INTERFERONS ,Logistic Models ,030104 developmental biology ,Haplotypes ,Liver ,Multivariate Analysis ,Immunology ,SOLID-ORGAN ,Interferons ,medicine.symptom ,IL28B GENE - Abstract
The International Liver Disease Genetics Consortium (ILDGC)., Genetic variation in the IFNL3–IFNL4 (interferon-λ3–interferon-λ4) region is associated with hepatic inflammation and fibrosis1,2,3,4. 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)5,6 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., M.E., M.D., and J.G. are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, and by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1053206) and NHMRC Project Grants (APP1107178 and APP1108422). G.D. is supported by an NHMRC Fellowship (1028432).
- Published
- 2017
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