Abstract
Humans are polymorphic in their ability to produce type-III interferons. Most individuals of African ancestry are genetically capable of generating all 4 type-III interferons (IFN-λ1, 2, 3, and 4), whereas the majority of individuals of European and Asian ancestry lack IFN-λ4 and thus can generate only IFN-λ1, 2, and 3. All 4 type-III IFNs are encoded by genes located within a ∼55 kb genomic region on human chromosome 19. Although IFN-λ4 appears to be important in animals, genetic alterations acquired in the Hominidae lineage, and particularly in humans, resulted in the elimination of IFN-λ4 or restriction of its activity, suggesting that IFN-λ4 function might be detrimental to human health. Genetic variants within the IFNL region, including those controlling production and activity of IFN-λ4, have been strongly associated with clearance of hepatitis C virus (HCV) infection. There is growing evidence for association of the same genetic variants with a multitude of other disease conditions. This article reviews the genetic landscape of the human IFNL genetic locus, with an emphasis on the genetic control of IFN-λ4 production and activity, and its association with viral clearance.
Highlights
The IFNL locus has attracted considerable attention due to the strong association of genetic variants in this region with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection
These results indicate that higher IFNL3 stability is either irrelevant or not as favorable for HCV clearance as it thought to be, or that rs368234815 and rs4803217 might have functional effects in different conditions
The genome-wide association studies (GWASs) findings a decade ago resulted in the discovery of a novel human interferon, IFN-l4, in 2013 and reinvigorated interest to other type-III interferons (IFN-l1, 2, and 3), discovered in 2002
Summary
Humans are polymorphic in their ability to produce type-III interferons. Most individuals of African ancestry are genetically capable of generating all 4 type-III interferons (IFN-l1, 2, 3, and 4), whereas the majority of individuals of European and Asian ancestry lack IFN-l4 and can generate only IFN-l1, 2, and 3. All 4 type-III IFNs are encoded by genes located within a *55 kb genomic region on human chromosome 19. Genetic variants within the IFNL region, including those controlling production and activity of IFN-l4, have been strongly associated with clearance of hepatitis C virus (HCV) infection. This article reviews the genetic landscape of the human IFNL genetic locus, with an emphasis on the genetic control of IFN-l4 production and activity, and its association with viral clearance
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