Interferon lambda 3 (gene symbol:IFNL3) encodes the IFNL3 protein.IFNL3 was formerly namedIL28B, but the Human Genome Organization Gene Nomenclature Committee renamed this gene in 2013 while assigning a name to the then newly discoveredIFNL4 gene.[5] Together withIFNL1 (formerlyIL29) andIFNL2 (formerlyIL28A), these genes lie in a cluster on chromosomal region 19q13. IFNL3 shares ~96% amino-acid identity with IFNL2, ~80% identity with IFNL1 and ~30% identity with IFNL4.
Interferon lambda genes encodecytokines classified astype III interferons, which are distantly related totype I interferons and theIL-10 family. Type III interferons are induced by viral infection and interact with a heterodimeric class II cytokine receptor that consists of interleukin 10 receptor, beta (IL10RB) and interferon lambda receptor 1 (IFNLR1) to signal via the JAK-STAT anti-viral pathway. [provided byRefSeq, Jul 2008].
In 2009 (i.e., before the discovery ofIFNL4), results fromgenome wide association studies (GWAS) indicated thatsingle-nucleotide polymorphisms (SNPs) lying nearIFNL3 (rs12979860, rs8099917 and others) were strongly associated with response to pegylated interferon-α andribavirin treatment for chronic hepatitis C,[6][7][8][9] as well as spontaneous clearance ofhepatitis C (HCV) infection.[10][11][12][13] The gene then known asIL28B (nowIFNL3) was the closest known gene at the time, so these genetic variants were called "IL28B variants." It was assumed that the observed associations reflected differences in the structure or regulation of that gene. However, discovery ofIFNL4 revealed that the rs12979860 SNP is located within intron 1 ofIFNL4, while rs8099917 lies in anintergenic region, but nearest toIFNL4.[5] The rs12979860 and rs8099917 SNPs are in highlinkage disequilibrium with a variant ofIFNL4 (IFNL4-ΔG/TT; rs368234815) that controls generation of the IFNL4 protein.[5]IFNL4-ΔG/TT appears to be the functional polymorphism that accounts for GWAS associations of nearby SNPs with HCV clearance, andIFNL4-ΔG/TT was shown to have stronger statistical association with HCV clearance than that of rs12979860, especially in populations of African ancestry in which linkage disequilibrium between these variants is weaker than in other populations.[5][14]
One possible functional variant inIFNL3 is the rs4803217 SNP, which lies in the 3' untranslated regulatory region. Substitution of guanine for the ancestral thymine at this site increasesIFNL3 mRNA expression by decreasing mRNA degradation and HCV-induced microRNA binding[15] and changes the RNA structure.[16][11] High linkage disequilibrium exists between rs4803217 and theIFNL4-ΔG/TT variant.[5] rs4803217 has been shown to associate with HCV clearance,[16] however, that association appears to stem from linkage disequilibrium withIFNL4-ΔG/TT rather than a direct functional effect of the rs4803217 SNP itself.
^Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. (October 2009). "IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy".Nature Genetics.41 (10):1100–4.doi:10.1038/ng.447.PMID19749758.S2CID21619093.
^Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. (October 2009). "Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C".Nature Genetics.41 (10):1105–9.doi:10.1038/ng.449.PMID19749757.S2CID20399078.
^Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. (April 2010). "Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study".Gastroenterology.138 (4):1338–45, 1345.e1-7.doi:10.1053/j.gastro.2009.12.056.PMID20060832.S2CID25546833.
Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. (January 2003). "IL-28, IL-29 and their class II cytokine receptor IL-28R".Nature Immunology.4 (1):63–8.doi:10.1038/ni873.PMID12469119.S2CID35764259.
Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. (January 2003). "IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex".Nature Immunology.4 (1):69–77.doi:10.1038/ni875.PMID12483210.S2CID2734534.
Li M, He S (April 2006). "Purification and characterization of recombinant human interleukin-29 expressed in Escherichia coli".Journal of Biotechnology.122 (3):334–40.doi:10.1016/j.jbiotec.2005.11.019.PMID16413080.
