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The role of IFNL4 in liver inflammation and progression of fibrosis

Genes & Immunity volume 23, pages 111–117 (2022)Cite this article

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Abstract

The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today.

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Fig. 1: The genomic organization of the IFNL loci and its variations.
Fig. 2: Pairwise linkage disequilibrium for SNPs in the IFNL3/IFNL4 region (chr19:39,238,300-39,255,100).

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Acknowledgements

The authors thank Dr Marc Ghany and Dr Ludmila Prokunina-Olsson for their helpful comments on an earlier draft of this paper. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The content of this publication and the opinions expressed reflect those of the individual authors solely and do not necessarily reflect the views or policies of the Department of Health and Human Services, the National Institutes of Health, the National Cancer Institute or the Food and Drug Administration nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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  1. Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, 8000, Aarhus C, Denmark

    Michelle Møhlenberg & Rune Hartmann

  2. Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

    Thomas R. O’Brien

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MM, TRO, and RH contributed to the paper draft. MM performed the literature search and created figures. The final version of this paper was reviewed and approved by all authors.

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Correspondence to Rune Hartmann.

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TRO’B is a coinventor on patents for the IFN-λ4 protein that are held by the National Cancer Institute. MM and RH have no competing interests to declare.

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Møhlenberg, M., O’Brien, T.R. & Hartmann, R. The role of IFNL4 in liver inflammation and progression of fibrosis. Genes Immun 23, 111–117 (2022). https://doi.org/10.1038/s41435-022-00173-9

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