Genetics of the Human Interferon Lambda Region

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.

IFN-λ4 is associated with increased risk and earlier occurrence of gastrointestinal, respiratory and malarial infections in Malian children

“…Humans have four type III IFNs, all encoded within the 70 kb region on chromosome 19. Three of these IFNs (IFN-λ1-3) can be inducibly generated in all the individuals, while IFN-λ4 is produced only in about 50% of the world population, including 90% of individuals of African ancestry, versus only 50% of Europeans and 10% of Asians (5, 8). The ability to produce IFN-λ4 is an ancestral trait, which appears to be under negative selection in humans (9).…”

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

“…All four type III IFN-λs (IFN-λ 1-4) are produced by a majority of people of African descent. In contrast, only IFN-λs 1-3 are produced by most people of European and Asian descent [90].…”

“…Despite its antiviral activities, functional IFN-λ4 has a negative impact on IFN-α-based HCV treatments ( Figure 2) [90]. A suboptimal treatment response to pegylated IFN-α in HCV infections was primarily associated with the IFNL4-∆G allele [3,25,89].…”

Interferon-lambda (IFNL) germline variations and their significance for HCC and PDAC progression: an analysis of The Cancer Genome Atlas (TCGA) data

“…Among the genes encoding IFN species, only one, type III IFNL4 , harbors a common exonic gain-or-loss-of-function variation: while the phylogenetically older variant ΔG enables functional IFN-λ 4 protein expression, the knockout variant TT causes a frameshift thereby disrupting the open reading frame and preventing translation [ 9 , 10 ]. This germline dinucleotide polymorphism, IFNL4 rs368234815 [TT/ΔG] (merged into IFNL4 rs11322783) thus reflects the ongoing process of pseudogenization dividing human beings into those who are predisposed to express IFN-λ 4 protein and into those who are not [ 11 ]; it associates with clearance of hepatitis C virus (HCV) and a variety of other disease conditions (reviewed in [ 12 ]).…”