Interferon lambda 3 (gene symbol: ''IFNL3)'' encodes the IFNL3 protein. ''IFNL3'' was formerly named ''IL28B'', but the Human Genome Organization Gene Nomenclature Committee renamed this gene in 2013 while assigning a name to the then newly discovered
''IFNL4'' gene.
Together with ''IFNL1'' (formerly ''IL29'') and ''IFNL2'' (formerly ''IL28A''), 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 encode
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s classified as
type III interferons, which are distantly related to
type I interferons and the
IL-10 family
The IL10 family is a family of interleukins.
In addition to IL-10, it includes IL-19, IL-20, IL-22, IL-24 and IL-26.
Some sources also include the interferons IL-28 and IL-29.
The IL-10 family are helical cytokines categorized based on ...
. 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.
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__Hepatitis_C_
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Hepatitis C
In 2009 (i.e., before the discovery of ''IFNL4''), results from Genome-wide association study">genome wide association studies (GWAS) indicated that single-nucleotide polymorphisms (SNPs) lying near ''IFNL3'' (rs12979860, rs8099917 and others) were strongly associated with response to pegylated interferon-α and ribavirin treatment for chronic hepatitis C, as well as spontaneous clearance of
hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
(HCV) infection.
The gene then known as ''IL28B'' (now ''IFNL3)'' 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 of ''IFNL4'' revealed that the rs12979860 SNP is located within intron 1 of ''IFNL4'', while rs8099917 lies in an
intergenic region
An intergenic region is a stretch of DNA sequences located between genes. Intergenic regions may contain functional elements and junk DNA. ''Inter''genic regions should not be confused with ''intra''genic regions (or introns), which are non-cod ...
, but nearest to ''IFNL4.''
The rs12979860 and rs8099917 SNPs are in high
linkage disequilibrium
In population genetics, linkage disequilibrium (LD) is the non-random association of alleles at different loci in a given population. Loci are said to be in linkage disequilibrium when the frequency of association of their different alleles is h ...
with a variant of ''IFNL4'' (''IFNL4-''ΔG/TT; rs368234815) that controls generation of the IFNL4 protein.
''IFNL4-''ΔG/TT appears to be the functional polymorphism that accounts for GWAS associations of nearby SNPs with HCV clearance, and ''IFNL4-''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.
One possible functional variant in ''IFNL3'' is the rs4803217 SNP, which lies in the 3’ untranslated regulatory region''.'' Substitution of guanine for the ancestral thymine at this site increases ''IFNL3'' mRNA expression by decreasing mRNA degradation and HCV-induced microRNA binding
and changes the RNA structure.
High linkage disequilibrium exists between rs4803217 and the ''IFNL4-''ΔG/TT variant.
rs4803217 has been shown to associate with HCV clearance,
however, that association appears to stem from linkage disequilibrium with ''IFNL4-''ΔG/TT rather than a direct functional effect of the rs4803217 SNP itself.
References
Further reading
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