Interferon lambda 4 genotype determines baseline expression of interferon-stimulated genes and lipid metabolism-related genes in the healthy liver 2304507

Introduction Interferon lambda 4 is an ancestral protein produced in the presence of the rs368234815-delta-G allele. This haplotype has been associated with decreased inflammation and disease progression in chronic hepatitis C and metabolic dysfunction-associated steatohepatitis. Methods To investigate the underlying mechanism, we performed single-cell RNA sequencing of liver biopsies from 14 subjects who were cured of chronic hepatitis C five years earlier. Results Twelve patients encoded IFN-lambda4 (rs368234815 delta-G/delta-G or delta-G/TT). Two of these patients encoded a functionally attenuated IFN-lambda4 protein, due to a P70S substitution (rs117648444-A/G). Two patients did not encode IFN-lambda4 (rs368234815-TT/TT). Interferon-stimulated gene expression was significantly higher in hepatocytes and liver sinusoidal endothelial cells of patients who produced IFN-lambda4 than in those who did not. Patients with a functionally attenuated IFN-lambda4 had significantly lower expression of interferon-stimulated genes than those with conserved IFN-lambda4 but higher expression than those without IFN-lambda4. These results extended to all intrahepatic immune cell populations, including T and NK cells that do not express IFNLR1. This suggests the induction of secondary type I and II IFN responses downstream of IFN-lambda4, which was confirmed by Hallmark gene enrichment analysis. Clinical data from a larger cohort of genotyped patients that had been cured of chronic hepatitis C (n = 44, male:28) revealed higher serum ALT activity in healthy male patients with IFN-lambda4 expression than those without, which was associated with an enrichment of the fatty acid degradation pathway and depletion of the steroid biosynthesis pathway in hepatocytes (KEGG database). Conclusion IFN-lambda4 induces interferon-stimulated gene expression in immune cells, endothelial cells, and hepatocytes in the liver, with a secondary effect on lipid metabolism in hepatocytes. Funding Source Intramural Research Program of NIDDK, NIH Topic Categories Immune Mechanisms of Human Disease (HUM)