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

• Published in: Nature genetics Vol. 49; no. 5; pp. 795 - 800
• Main Authors: Eslam, Mohammed, McLeod, Duncan, Kelaeng, Kebitsaone Simon, Mangia, Alessandra, Berg, Thomas, Thabet, Khaled, Irving, William L, Dore, Gregory J, Sheridan, David, Grønbæk, Henning, Abate, Maria Lorena, Hartmann, Rune, Bugianesi, Elisabetta, Spengler, Ulrich, Rojas, Angela, Booth, David R, Weltman, Martin, Mollison, Lindsay, Cheng, Wendy, Riordan, Stephen, Mahajan, Hema, Fischer, Janett, Nattermann, Jacob, Douglas, Mark W, Liddle, Christopher, Powell, Elizabeth, Romero-Gomez, Manuel, George, Jacob
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2017; Nature Publishing Group
• Subjects: 38/77; 631/208; 631/208/212; 692/699/1503/234; Agriculture; Animal Genetics and Genomics; Biomedicine; Cancer Research; Consortia; Fibrosis; Fibrosis - genetics; Fibrosis - metabolism; Gastroenterology; Gene Frequency; Gene Function; Genetic diversity; Genetics; Genomes; Genotype; Haplotypes; Hepacivirus - physiology; Hepatitis; Hepatitis C - genetics; Hepatitis C - virology; Hepatology; Hospitals; Human Genetics; Humans; Immune system; Infections; Infectious diseases; Infiltration; Inflammation; Inflammation - genetics; Inflammation - metabolism; Interferon; Interferons; Interleukins - genetics; Interleukins - metabolism; letter; Linkage Disequilibrium; Liver; Liver - metabolism; Liver - pathology; Liver diseases; Logistic Models; Macrophages; Medical research; Multivariate Analysis; Polymorphism, Single Nucleotide; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Studies; γ-Interferon
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3836

Jacob George and colleagues examine whether the association of the
IFNL3
–
IFNL4
region with hepatic inflammation and fibrosis is mediated by IFN-λ3 or IFN-λ4. They find greater hepatic inflammation, fibrosis progression rate and hepatic infiltration of immune cells in individuals with the risk haplotype that produces IFN-λ3 but not IFN-λ4.
Genetic variation in the
IFNL3
–
IFNL4
(interferon-λ3–interferon-λ4) region is associated with hepatic inflammation and fibrosis
1
,
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.