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

Nature Genetics volume 49, pages 795–800 (2017)Cite this article

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Abstract

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.

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Figure 1: Schematic of the IFNL3 and IFNL4 genes and genetic variants.
Figure 2: Univariate Cox regression analysis of association of IFNL3 and IFNL4 variants or IFN-λ4 activity with fibrosis progression.
Figure 3: Correlation of IFNL3 and IFNL4 variants and inflammatory cells in liver biopsy specimens with serum sCD163 levels.
Figure 4: Absolute quantification of IFNL3 mRNA by ddPCR in human liver.

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Acknowledgements

We would like to thank all the patients for their participation in this study. 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).

Author information

Authors and Affiliations

  1. Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia

    Mohammed Eslam, Kebitsaone Simon Kelaeng, Khaled Thabet, Mark W Douglas, Christopher Liddle, Jacob George, Mayada Metwally, Rose White, Reynold Leung, Antony Rahme & Anastasia Asimakopoulos

  2. Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia

    Duncan McLeod, Hema Mahajan & Neha Mahajan

  3. Division of Hepatology, Ospedale Casa Sollievo della Sofferenza, IRCCS, San Giovanni Rotondo, Italy

    Alessandra Mangia & Rosanna Santoro

  4. Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany

    Thomas Berg, Janett Fischer & Barbara Malik

  5. Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt

    Khaled Thabet

  6. NIHR Biomedical Research Unit in Gastroenterology and the Liver, University of Nottingham, Nottingham, UK

    William L Irving

  7. Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia

    Gregory J Dore, Gail Matthews, Tanya Applegate, Jason Grebely & Julie R Jonsson

  8. Institute of Translational and Stratified Medicine, Plymouth University, Plymouth, UK

    David Sheridan & Margaret Bassendine

  9. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    Henning Grønbæk

  10. Division of Gastroenterology and Hepatology, Department of Medical Science, University of Turin, Turin, Italy

    Maria Lorena Abate, Elisabetta Bugianesi, Chiara Rosso & Lavinia Mezzabotta

  11. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Rune Hartmann

  12. Department of Internal Medicine I, University of Bonn, Bonn, Germany

    Ulrich Spengler, Jacob Nattermann & Vincenzo Fragomeli

  13. UCM IC Digestive Diseases and ciberehd. University Hospital Virgen del Rocio, Institute of Biomedicine of Seville, Seville, Spain

    Angela Rojas, Manuel Romero-Gomez & Rocio Gallego-Duran

  14. Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia

    David R Booth

  15. Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, New South Wales, Australia

    Martin Weltman

  16. Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, Western Australia, Australia

    Lindsay Mollison

  17. Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia

    Wendy Cheng

  18. Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales, Australia

    Stephen Riordan

  19. Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia

    Mark W Douglas

  20. University of Queensland, School of Medicine, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

    Elizabeth Powell

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  1. Mohammed Eslam
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Consortia

the International Liver Disease Genetics Consortium (ILDGC)

  • 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

Contributions

M.E. and J.G. conceived the research. Enrollment of patients, clinical phenotype and data collation, sample acquisition and DNA preparation, sCD163 measurement, ddPCR, and critical analysis were performed by M.E., A.M., T.B., K.T., W.L.I., G.J.D., D.S., H.G., M.L.A., R.H., E.B., U.S., A.R., D.R.B., M.W., L.M., W.C., S.R., J.F., J.N., M.W.D., C.L., E.P., M.R.-G., and J.G. Genotyping was performed by K.S.K. Histological analysis of tissues and scoring were conducted by D.M. and H.M. The manuscript was principally written and revised by M.E. and J.G. All authors critically reviewed the manuscript for important intellectual content and approved the final submitted manuscript.

Corresponding author

Correspondence to Jacob George.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Association between IFNL4 rs368234815, IFNL3 rs4803217, and IFNL4 rs117648444 genotype and serum sCD163 in 506 patients with chronic hepatitis C virus.

(a–c) The x axis shows genotype at rs368234815 using the dominant model of inheritance (TT = 223, TΔG/ΔGΔG = 283) (a), genotype at rs4803217 using the dominant model of inheritance (TT = 232, TG/GG = 274) (b), and genotype at rs117648444 (GG = 423, GA/AA = 83) (c). The y axis shows sCD163 expression level (mg/ml) by ELISA. The number of independent samples tested in each group is shown. Each group is represented as a box plot, and the median values are shown as thick dark horizontal lines. The box covers the 25th to 75th percentiles. We tested the difference in the median values between genotypes using two-tailed Mann–Whitney tests. We plotted the box plots using GraphPad Prism 7.

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Eslam, M., McLeod, D., Kelaeng, K. et al. IFN-λ3, not IFN-λ4, likely mediates IFNL3–IFNL4 haplotype–dependent hepatic inflammation and fibrosis. Nat Genet 49, 795–800 (2017). https://doi.org/10.1038/ng.3836

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