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

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 RiordanHema Mahajan, Janett Fischer, Jacob Nattermann, Mark W. Douglas, Christopher Liddle, Elizabeth Powell, Manuel Romero-Gomez, Jacob George, Mayada Metwally, Rose White, Rocio Gallego-Duran, Reynold Leung, Neha Mahajan, Margaret Bassendine, Antony Rahme, Chiara Rosso, Lavinia Mezzabotta, Barbara Malik, Gail Matthews, Anastasia Asimakopoulos, Tanya Applegate, Jason Grebely, Vincenzo Fragomeli, Julie R. Jonsson, Rosanna Santoro, International Liver Disease Genetics Consortium (ILDGC)

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)795-800
Number of pages6
JournalNature Genetics
Volume49
Issue number5
DOIs
Publication statusPublished - May 1 2017

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ASJC Scopus subject areas

  • Genetics

Cite this

Eslam, M., McLeod, D., Kelaeng, K. S., Mangia, A., Berg, T., Thabet, K., Irving, W. L., Dore, G. J., Sheridan, D., Grønbæk, H., Abate, M. L., Hartmann, R., Bugianesi, E., Spengler, U., Rojas, A., Booth, D. R., Weltman, M., Mollison, L., Cheng, W., ... International Liver Disease Genetics Consortium (ILDGC) (2017). IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis. Nature Genetics, 49(5), 795-800. https://doi.org/10.1038/ng.3836