IFN-lambda 3, not IFN-lambda 4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis

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DOI

  • Mohammed Eslam, Sydney University, Sydney
  • ,
  • Duncan McLeod, Sydney University, Sydney
  • ,
  • Kebitsaone Simon Kelaeng, Sydney University, Sydney
  • ,
  • Alessandra Mangia, IRCCS Casa Sollievo della Sofferenza
  • ,
  • Thomas Berg, Univ Leipzig, University of Leipzig, Inst Biol
  • ,
  • Khaled Thabet, Minia University
  • ,
  • William L Irving, Nottingham University
  • ,
  • Gregory J Dore, The University of New South Wales, Sydney
  • ,
  • David Sheridan, Plymouth University
  • ,
  • Henning Grønbæk
  • Maria Lorena Abate, University of Turin, Orbassano
  • ,
  • Rune Hartmann
  • Elisabetta Bugianesi, University of Turin, Orbassano
  • ,
  • Ulrich Spengler, Univ Bonn, University of Bonn, Dept Psychiat
  • ,
  • Angela Rojas, Univ Hosp Virgen del Rocio
  • ,
  • David R. Booth, Sydney University, Sydney
  • ,
  • Martin Weltman, Nepean Hosp
  • ,
  • Lindsay Mollison, University of Western Australia
  • ,
  • Wendy Cheng, University of Western Australia
  • ,
  • Stephen Riordan, The University of New South Wales, Sydney
  • ,
  • Hema Mahajan, Sydney University, Sydney
  • ,
  • Janett Fischer, Univ Leipzig, University of Leipzig, Inst Biol
  • ,
  • Jacob Nattermann, Univ Bonn, University of Bonn, Dept Psychiat
  • ,
  • Mark W Douglas, Sydney University, Sydney
  • ,
  • Christopher Liddle, Sydney University, Sydney
  • ,
  • Elizabeth Powell, University of Queensland, St. Cucia, Queensland
  • ,
  • Manuel Romero-Gomez, Univ Hosp Virgen del Rocio
  • ,
  • Jacob George, Sydney University, Sydney
  • ,
  • Int Liver Dis Genetics Consortium

Genetic variation in the IFNL3-IFNL4 (interferon-lambda 3-interferon-lambda 4) region is associated with hepatic inflammation and fibrosis1-4. Whether IFN-lambda 3 or IFN-lambda 4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-lambda 3 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-lambda 4, but produces IFN-lambda 3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-lambda 4 protein and reduces IFN-lambda 4 activity, or between patients encoding functionally defective IFN-lambda 4 (IFN-lambda 4-Ser70) and those encoding fully active IFN-lambda 4-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-lambda 3 rather than IFN-lambda 4 likely mediates IFNL3-IFNL4 haplotypedependent hepatic inflammation and fibrosis.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind49
Nummer5
Sider (fra-til)795-800
Antal sider8
ISSN1061-4036
DOI
StatusUdgivet - maj 2017

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