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Interferon Lambda 4 Phenotypes

A collaboration led by DCEG investigators in the Infections and Immunoepidemiology Branch (IIB) and the Laboratory of Translational Genomics (LTG) led to the discovery of the interferon lambda 4 (IFNL4) gene (Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet 2013). Recent epidemiological studies have associated IFNL4 genotype with hepatic inflammation and fibrosis, which are precursors of hepatocellular carcinoma (HCC), as well as mucinous ovarian carcinoma, a rare cancer subtype of uncertain etiology. Evidence of strong evolutionary selection against the IFNL4-ΔG allele suggests IFNL4 could impact diseases besides HCV infection; recent studies in mice demonstrated that the interferon lambda family plays an important role in a wide range of infections. Taken together, these findings make IFNL4 a candidate gene for many infections and conditions. Recently, IIB investigators and their colleagues reported results from a study in which they examined the possible relationship between IFNL4 genotype and 16 opportunistic infections or malignancies in a large cohort of men who have sex with men and who were infected with human immunodeficiency virus type 1 (Fang MZ, Jackson SS, Pfeiffer RM, et al. No association of IFNL4 genotype with opportunistic infections and cancers among men with HIV-1 infection. Clin Infect Dis 2022).

IIB researchers have initiated additional investigations to examine the phenotypic range of the IFNL4 genotype, including a study of hepatic inflammation and fibrosis, which are precursors of hepatocellular carcinoma, and a phenome-wide association study for the IFNL4 genotype among patients enrolled in a large managed care organization.

For more information, contact Thomas O’Brien.
Infections and Immunoepidemiology Branch - Research Areas