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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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).
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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.
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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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DOI: https://doi.org/10.1038/ng.3836
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