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Published in final edited form as: Gene. 2019 Dec 14;730:144289. doi: 10.1016/j.gene.2019.144289

IFNL4: Notable Variants and Associated Phenotypes

Michelle Z Fang a, Sarah S Jackson a, Thomas R O’Brien a,*
PMCID: PMC8600600  NIHMSID: NIHMS1548832  PMID: 31846709

Abstract

Interferon lambda proteins activate the JAK-STAT signalling pathway, resulting in upregulation of genes with antiviral effects. The interferon lambda family was initially thought to be redundant to the interferon alpha family, which signals through the same pathway, except for the more limited expression of the IFNLR1 receptor. However, recent studies show that interferon lambdas uniquely protect tissue barriers against a wide range of important viral infections. The interferon lambda 4 gene (IFNL4) was discovered in 2013. The IFNL4 protein is determined by the IFNL4-ΔG/TT (rs368234815) variant. The ancestral IFNL4-ΔG allele generates IFNL4, whereas IFNL4-TT causes pre-mature termination of the protein. Surprisingly, although interferons are generally antiviral proteins, the genotypes that generate the IFNL4 protein are strongly linked to impaired clearance of hepatitis C virus (HCV). IFNL4 genotype has also been linked to variation within the HCV genome, as well as risk of hepatic fibrosis, certain cancers and some infectious disease. There has been very strong evolutionary selection against the ancestral IFNL4-ΔG allele, which is the major form in African populations, but the minor allele in Europeans and Asians. The reason for this selection and the biological mechanisms underlying observed phenotypic associations remain to be explained.

Keywords: hepatitis C virus, IFNL3, interferon lambda, liver, infectious disease

1. Introduction

First reported in 2013, interferon lambda 4 (gene symbol: IFNL4) is one of the most recently discovered human genes and the newest addition to the interferon lambda family. IFNL4 is similar to three neighboring genes (IFNL1, IFNL2 and IFNL3) in that proteins encoded by these genes bind to a shared co-receptor complex, leading to activation of the JAK-STAT signalling pathway and upregulation of numerous interferon-stimulated genes. Several polymorphisms within or near IFNL4 strongly associate with clearance of hepatitis C virus (HCV) infection and other phenotypes.

2. Interferon Lambda Genes

The first three interferon lambda genes were discovered by two independent research groups that used different nomenclatures in their reports (Kotenko et al., 2003; Sheppard et al., 2003). At that time in 2003, the Human Genome Organization Gene Nomenclature Committee (HUGO NC) adopted an interleukin designation for these genes, but the HUGO NC reconsidered that decision ten years later, recognizing them and a newly discovered fourth gene as interferon lambda genes. The official symbols for these genes are IFNL1 (formerly IL29), IFNL2 (formerly IL28A), IFNL3 (formerly IL28B) and IFNL4.

In 2009, results from genome wide association studies (GWAS) indicated that single nucleotide polymorphisms (SNPs) upstream of IFNL3 strongly associated with response to pegylated interferon-α and ribavirin treatment in patients infected with hepatitis C virus (HCV) (Ge et al., 2009; Suppiah et al., 2009; Tanaka et al., 2009), as well as with spontaneous clearance of HCV infection (Thomas et al., 2009; Rauch et al., 2010). It was assumed that these associations reflected differences in the structure or regulation of IFNL3. However, by conducting RNA sequencing of primary human hepatocytes that had been treated with polyinosinic:polycytidylic acid (poly I:C), our group of collaborating investigators revealed the presence of the IFNL4 gene, which had previously gone unrecognized (Prokunina-Olsson et al., 2013). Poly I:C mimics double stranded RNA, thereby, simulating HCV infection and inducing expression of interferon lambda (Lauterbach et al., 2010; Siegel, Eskdale, & Gallagher, 2011).

The interferon lambda genes lie in the 19q13.13 chromosomal region (Figure 1). IFNL4 is located between IFNL3 and IFNL2. The IFNL4 gene contains five exons (Figure 2), and the full IFNL4 protein consists of 179 amino acids (Prokunina-Olsson et al., 2013).

Figure 1.

Figure 1.

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Location of single nucleotide polymorphisms (SNPs) associated with HCV clearance in genome wide association studies of hepatitis C virus clearance. The rs12979860 SNP lies in intron 1 of IFNL4 and rs8099917 lies upstream of IFNL4.

Figure 2.

Figure 2.

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Functional variants in the IFNL4 gene. The IFNL4-ΔG/TT (rs368234815) variant lies in exon 1 and IFNL4 P70S (rs117648444) lies exon 2.

The proteins encoded by the IFNL1, IFNL2, and IFNL3 genes have a high amino-acid sequence similarity (Kotenko et al., 2003; Sheppard et al., 2003). IFNL2 and IFNL3 share ~96% amino-acid identity, and IFNL1 shares ~81% identity with IFNL2 and IFNL3. In contrast, IFNL4 differs considerably from other members of this family. IFNL4 is most closely related to IFNL3, however, these proteins share only ~30% amino-acid identity (Prokunina-Olsson et al., 2013). Similarity between IFNL3 and IFNL4 is greatest for the A and F helices, where lambda interferons interact with the IFNLR1 receptor, and least in the D helix, where they interact with IL10R2, the second component of the interferon lambda receptor complex (Prokunina-Olsson et al., 2013).

3. Notable Genetic Variants Within and Near IFNL4

SNPs associated with HCV clearance in GWAS (rs12979860, rs8099917, and others) were initially considered IL28B (IFNL3) variants, based on proximity to that gene, however, the discovery of IFNL4 revealed that these genetic markers lie within or nearest to IFNL4. The rs12979860 SNP is located within intron 1 of IFNL4; rs8099917 lies in an intergenic region, but nearest to IFNL4 (Figure 1) (Prokunina-Olsson et al., 2013). These SNPs are yet often erroneously referred to as IL28B or IFNL3 variants, and that confusion may handicap investigators in efforts to understand functional mechanisms underlying phenotypic associations with polymorphisms in this genetic region.

The discovery of IFNL4 yielded genetic insights extending well beyond better localization of the GWAS marker SNPs associated with HCV clearance. IFNL4 contains an important and unusual polymorphism that controls the generation of the IFNL4 protein. (Figure 2). The IFNL4-ΔG/TT (rs368234815, previously ss469415590) variant lies in exon 1 of IFNL4. This dinucleotide polymorphism is comprised of the rs11322783 (Δ/T) and rs74597329 (G/T) SNPs. These two SNPs are in full linkage disequilibrium, therefore, rs368234815, rs11322783 and rs74597329 all provide the same information. In the NCBI dbSNP database, rs368234815 been merged into rs11322783. Neither rs368234815 nor rs11322783 are present in the Genome Aggregation Database, where IFNL4-ΔG/TT is represented by rs74597329.

The ancestral IFNL4-ΔG allele creates an open reading frame that allows the full length IFNL4 protein to be made, while the alternative IFNL4-TT allele results in a frameshift at amino acid position 22 that prematurely terminates the protein (Prokunina-Olsson et al., 2013). The IFNL4-TT allele produces peptides of 51, 75 and 123 amino acids that are subject to nonsense-mediated decay, which decreases the level of their expression. These polypeptides have no known biological function (Prokunina-Olsson et al., 2013). Although the IFNL4 gene is present in all primates (and most non-primate mammals except mice or rats) (Paquin, Onabajo, Tang, & Prokunina-Olsson, 2016), humans are the only species in which the allele that abrogates IFNL4 has been found.

Among all chromosomal regions that contain human interferon genes, the interferon lambda region has undergone the strongest selection (Manry et al., 2011). Specifically, there has been very strong evolutionary selection for the IFNL4-TT variant, which ‘knocks out’ production of the IFNL4 protein (Key et al., 2014). This allele likely arose just before the out-of-Africa migration and underwent immediate selection in the African population. That selection strengthened in European and Asian populations. As a result, whereas ~95% of individuals of African ancestry carry at least one copy of the IFNL4-ΔG allele, this percentage drops to ~50% in Europeans and <15% in Asians (Prokunina-Olsson et al., 2013). Comparison of African and East Asian populations reveals the IFNL4-TT allele to be among the most differentiated variants genome-wide (Key et al., 2014). It is unlikely HCV infection exerted the selection pressure that created these striking differences, as HCV did not become common until the twentieth century, and chronic HCV infection has too long of a course to majorly impact reproduction (O’Brien, Prokunina-Olsson, & Donnelly, 2014).

The IFNL4-ΔG/TT variant is in linkage disequilibrium with the rs12979860 and rs8099917 SNPs (Figure 3) (Prokunina-Olsson et al., 2013). Linkage disequilibrium between IFNL4-ΔG/TT and IFNL4 rs12979860 is complete in Asian populations (r2=1.0) and strong among those of European (r2>0.9), but weaker in African populations (r2~0.7) (Prokunina-Olsson et al., 2013). For rs8099917, linkage disequilibrium with IFNL4-ΔG/TT is strong in Asian populations, moderate in Europeans, and weak in Africans (Figure 3) (Prokunina-Olsson et al., 2013).

Figure 3.

Figure 3.

Figure 3.

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Linkage disequilibrium plots of the IFNL4-ΔG/TT (rs368234815), rs12979860, and IFNL4 P70S (rs8099917) variants among A) African, B) European, and C) East Asian reference populations (1000 Genomes Project version 5). Linkage disequilibrium values are highest for individuals of East Asian ancestry and lowest for individuals of African ancestry.

On the whole, the interferon lambda region variants that most strongly associate with HCV clearance lie within or nearest to IFNL4, however, a plausible functional polymorphism is found within the regulatory 3’ untranslated region of IFNL3. Substitution of guanine for the ancestral thymine in the rs4803217 SNP increases IFNL3 mRNA expression by decreasing mRNA degradation and HCV-induced microRNA binding (McFarland et al., 2014). Similar to rs12979860, rs4803217 is in very high linkage disequilibrium with the IFNL4-ΔG/TT variants in European and East Asian populations and in more modest linkage disequilibrium with IFNL4-ΔG/TT in African populations (Figure 3).

Table 1 shows haplotypes that are formed by these interferon lambda variants (Machiela & Chanock, 2015). In Africans, the ancestral haplotype (rs4803217-T:rs12979860-T:IFNL4-ΔG:rs8099917-T) is most common (frequency ~61%). In contrast, the haplotype comprised of rs4803217-G, rs12979860-C, IFNL4-TT, and rs8099917-T is the most frequent form in Europeans (frequency ~69%) and East Asians (frequency ~92%). Therefore, the major haplotype differs markedly by race, and the rs8099917-T allele is linked to the IFNL4-TT allele in European and Asians, but not in Africans.

Table 1.

Haplotype frequencies from Version 5 of the 1000 Genomes Project using LDLink in Africans, Europeans, and East Asians

rs4803217 rs12979860 rs368234815 rs8099917 Haplotype Frequency (%)
Africans Haplotypes T T ΔG T 61
G C TT T 28.4
T T ΔG G 4.0
G C ΔG T 3.7
G T ΔG T 1.6
T C TT T 0.8
Total Allele Frequency (%) T=66.0, G=34.0 T=66.9, C=33.1 ΔG=70.7, TT=29.3 T=95.8, G=4.2
Europeans Haplotypes G C TT T 68.7
T T ΔG G 16.2
T T ΔG T 14.4
Total Allele Frequency (%) T=30.8, G=69.2 T=30.9, C=69.1 ΔG=31.2, TT=68.8 T=83.2, G=16.8
East Asians Haplotypes G C TT T 91.7
T T ΔG G 7.5
T T ΔG T 0.5
Total Allele Frequency (%) T=8.2, G=91.8 T=8.0, C=92.0 ΔG=8.0, TT=92.0 T=92.4, G=7.6
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There is evidence for another important functional polymorphism within IFNL4. A non-synonymous variant located in exon 2 (rs117648444) substitutes a serine for a proline at amino acid position 70 (P70S) when present on a haplotype that includes the IFNL4-ΔG allele (Prokunina-Olsson et al., 2013). The IFNL4-ΔG/TT and rs117648444 variants present in three observed haplotypes: IFNL4-ΔG: rs117648444-G, which creates the IFNL4 P70 protein; IFNL4-ΔG: rs117648444-A, which creates the IFNL4 S70 protein; IFNL4-TT: rs117648444-G, which does not generate a full IFNL4 protein (Prokunina-Olsson et al., 2013; Terczynska-Dyla et al., 2014). The frequencies of these haplotypes in different racial groups are shown in table 2. In vitro studies have demonstrated the IFNL4 S70 protein has weaker biological function than IFNL4 P70. Specifically, IFNL4 S70 produced lower levels of interferon-stimulated gene expression and less antiviral activity against encephalomyocarditis virus compared to IFNL4 P70 (Terczynska-Dyla et al., 2014).

Table 2.

IFNL4-ΔG/TT and P70S haplotype frequencies from Version 5 of the 1000 Genomes Project using LDLink in Africans, Europeans, and East Asians

rs368234815 rs117648444 Haplotype Frequency (%)
Africans Haplotypes ΔG G 63.2
TT G 29.4
ΔG A 7.5
Europeans Haplotypes TT G 68.8
ΔG G 19.4
ΔG A 11.8
East Asians Haplotypes TT G 92.0
ΔG G 7.5
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Two other nonsynonymous variants of IFNL4 are rs73555604 (C17T) in exon 1 and rs142981501 (R60P) in exon 2 (Prokunina-Olsson et al, 2013). As these variants are present on haplotypes that encode IFNL4, they may represent additional evolutionary mechanisms to modulate the activity of IFNL4 (Prokunina-Olsson, 2019). The frequency of C17Y frequency is high in African populations (26%), but low in other groups. R60P is present at low allele frequency in individuals of African ancestry and has not been found in other populations (Prokunina-Olsson et al 2013).

4. Associated Phenotypes

4.1. Spontaneous HCV Clearance and Response to Therapy for Chronic Hepatitis C

About 15–25% of individuals who are infected with HCV clear the virus spontaneously, but most develop chronic hepatitis C, which increases risk of liver cancer, cirrhosis and other conditions (Liang, Rehermann, Seeff, & Hoofnagle, 2000). Previously, treatment for chronic hepatitis C usually consisted of extended therapy with pegylated interferon-α and ribavirin, however, that regimen cured only ~50% of patients and was associated with common, serious, adverse effects. Recently, therapy for chronic hepatitis C has undergone a major advance with the availability of direct acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication and assembly. Genotype for the IFNL4-ΔG/TT variant, as well as for SNPs in linkage disequilibrium with that polymorphism, associate with both spontaneous clearance of HCV infection and successful treatment of chronic hepatitis C.

As noted above, interferon lambda became a focus of HCV research when studies associated the rs12979860 and rs8099917 SNPs with response to pegylated interferon-α and ribavirin for chronic hepatitis C patients, (Ge et al., 2009; Suppiah et al., 2009; Tanaka et al., 2009) as well as with spontaneous HCV clearance (Thomas et al., 2009; Rauch et al., 2010). Compared to populations of European or Asian ancestry, African American populations demonstrated a lower frequency of the rs12979860-CC genotype (Ge et al., 2009; Thomas et al., 2009), which is associated with viral clearance. That observation provided an explanation for previously observed racial differences in HCV treatment response and spontaneous clearance (Muir, Bornstein, & Killenberg, 2004; Conjeevaram et al., 2006). The demonstrated association between genotype for the rs12979860 SNP and treatment led the US Food and Drug Administration to recommend assessment for “IL28B” in clinical trials for new chronic hepatitis C treatments (Pacanowski, Amur, & Zineh, 2012). Studies have been predominantly conducted on HCV genotype 1, but the association between IFNL4 genotype and impaired HCV clearance has been observed for other HCV genotypes as well (Li, Yang, Sha, Liu, & Zhang, 2016; Pedergnana, Irving, Barnes, McLauchlan, & Spencer, 2019).

High linkage disequilibrium between marker SNPs and candidate explanatory genetic variants present a challenge in identifying functional polymorphisms that account for GWAS findings. The weaker linkage disequilibrium between IFNL4-ΔG/TT and IFNL4 rs12979860 observed in populations of African ancestry facilitated comparison of those polymorphisms for associations with HCV clearance. Findings among African American populations that IFNL4-ΔG/TT was a better predictor than rs12979860 for both response to pegylated interferon-α/ribavirin therapy and spontaneous HCV clearance provided evidence for IFNL4-ΔG/TT as the primary functional variant in HCV clearance (Prokunina-Olsson et al., 2013; Aka et al., 2014). These findings have been confirmed in a larger study of spontaneous clearance in an African American population (Vergara et al., 2019) and also in extended to European populations (Stéphanie Bibert et al., 2013; Franco et al., 2014).

Associations between HCV clearance and genotype for the IFNL4-ΔG/TT polymorphism are strong. Among patients enrolled in the Virahep-C trial, odds ratios for achieving a sustained virological response after treatment pegylated-interferon alpha/ribavirin (IFNL4-TT/TT versus IFNL4- ΔG/ΔG) were 2.90 (P=0.07) and 4.42 (P=0.005) in African-Americans and European-Americans, respectively (Prokunina-Olsson et al., 2013). In the HALT-C cohort, even larger odds ratios were observed: 11.0 (P=0.03) and 6.94 (P<0.001) for sustained viral response among African-Americans and European-Americans, respectively (Prokunina-Olsson et al., 2013).

Despite the fact that interferon-stimulated genes upregulated by JAK-STAT signalling have antiviral properties, greater induction of these genes in liver tissue was linked to poorer HCV treatment success rates (Chen et al., 2005; Feld et al., 2007; Sarasin-Filipowicz et al., 2008). That the IFNL4-ΔG allele (determined directly or through knowledge of linkage) associates with both higher levels of interferon-stimulated gene mRNA and poorer treatment response (Honda et al., 2010; Urban et al., 2010) seems to explain this relationship.

Genotype for the SNP (rs117648444) that controls the IFNL4 P70S protein variant also associates with HCV clearance. In in vitro studies, the derived IFNL4 S70 protein produces reduced intrahepatic interferon stimulating gene expression and antiviral activity relative to IFNL4 P70 (Terczynska-Dyla et al., 2014). In population studies, the variant that creates IFNL4 S70 associates with increased rates of spontaneous HCV clearance and better treatment response (Galmozzi & Aghemo, 2014; Terczynska-Dyla et al., 2014). These results provide additional evidence that reduced IFNL4 activity improves HCV clearance.

The IFNL3 3’ untranslated region variant (rs4803217) has also been proposed as a functional variant underlying the GWAS findings for HCV clearance (McFarland et al., 2014). Investigating this question in an African American study population with relatively low linkage disequilibrium between the IFNL4-ΔG/TT and rs4803217 variants, we found that genotype for IFNL4-ΔG/TT displayed the stronger association with HCV clearance. In a haplotype analysis, the rs4803217-G allele, which increases IFNL3 mRNA expression, associated with poor HCV clearance (O’Brien et al., 2015).

4.2. Selection for HCV Variants

Other recent studies provide evidence that IFNL4 genotype may affect the HCV viral genome. The HCV NS5A protein is targeted by certain DAAs and variants in which histidine is substituted for tyrosine at amino acid position 93 (NS5A Y93H) may cause resistance to those agents. Patients with the NS5A Y93H variant are less likely to respond to NS5A inhibitors such as daclatasvir, ledipasvir and ombitasvir (Karino et al., 2013; Lontok et al., 2015), which are commonly used in popular DAA regimens (e.g., Harvoni). In a group of Japanese patients infected with the HCV 1b subtype, Akamatsu et al found that those with the IFNL4-TT/TT genotype had a higher frequency of the NS5A Y93H substitution than those who carried the ΔG allele (Akamatsu et al., 2015). Consistent with those results, other investigators found the IFNL4 rs12979860-C/C genotype was strongly associated with the prevalence of the Y93H variant in patients infected with HCV genotype 1b (Peiffer et al., 2016).

Ansari et al conducted a genome-to-genome analysis to examine the relationship between human genetic variants and variation in the HCV genome (Ansari et al., 2017). Most of the participants were infected with HCV genotype 3. They reported that genotype for IFNL4 rs12979860 associated with variation for many amino acids in the HCV genome and that HCV-infected patients with the rs12979860-CC genotype (i.e., those that do not generate the IFNL4 protein) had a higher frequency of non-synonymous HCV variants than patients with non-CC genotypes.

4.3. Hepatic Inflammation and Fibrosis

IFNL4 genotypes associated with increased HCV clearance and treatment response have also been linked to increased hepatic inflammation and fibrosis progression, which can lead to development of cirrhosis and liver cancer. In Europeans, the rs8099917-G allele is in high linkage disequilibrium with IFNL4-ΔG and associates with reduced HCV clearance. In a cohort of Swiss patients with chronic hepatitis C, Bochud and colleagues demonstrated that the rs8099917-G allele was associated with decreased necroinflammation, fibrosis and fibrosis progression (Bochud et al., 2012). In another longitudinal analysis of patients with chronic hepatitis C, individuals with the rs12979860-CC genotype displayed higher portal inflammation, although analysis of paired biopsy results did not reveal associations between this genotype and fibrosis progression (Noureddin et al., 2013). Extending those findings, Eslam et al found the rs12979860-CC genotype to be associated with increased inflammation and fibrosis not only in chronic HCV patients, but also in those with chronic hepatitis B or nonalcoholic fatty liver disease (Eslam et al., 2015).

In a study of HCV-infected African Americans and European ancestry patients undergoing liver transplantation, donor genotype for IFNL4-ΔG/TT was a stronger predictor of posttransplant fibrosis progression than genotype for rs12979860 (Aiken et al., 2016). In a second study by Eslam and colleagues, the investigators examined associations of the IFNL4-ΔG/TT, IFNL4 rs12979860, and IFNL3 3’ untranslated region (rs4803217) variants with hepatic inflammation and fibrosis among patients of European ancestry with chronic hepatitis C (Eslam et al., 2017). Linkage disequilibrium between those polymorphisms was too strong to discern genotype differences for the outcomes. The investigators also looked at whether genotype for IFNL4 P70S (rs117648444) associated with the degree of inflammation and fibrosis. In contrast to results from studies of HCV clearance, Eslam et al found no differences between genotypes that generated different variants of the IFNL4 protein for either fibrosis or inflammation.

4.4. Risk of Cancer

The many GWAS conducted for a wide range of malignancies should have been able to detect associations of IFNL4 genotype with cancer risk, however, in this large portfolio of studies, such an association is limited to risk of a rare subtype of ovarian cancer. GWAS performed by an international consortium revealed the IFNL4-ΔG allele, which generates the IFNL4 protein, was associated with a decreased risk of mucinous ovarian carcinoma (Kelemen et al., 2015). The explanation for this association remains to be determined.

On the other hand, in a candidate gene study, IFNL4-ΔG associated with an increased risk of prostate cancer among men with sexually transmitted infections (Minas et al., 2018; Tang et al., 2018). Kaposi’s sarcoma is an opportunistic malignancy caused by human herpesvirus 8 and seen at a high frequency among HIV-infected men who had sex with men. In a Swiss cohort, men who carried the rs8099917-G allele, which is in linkage disequilibrium with IFNL4-ΔG in European populations, had an increased risk of Kaposi’s sarcoma (S. Bibert et al., 2018).

4.5. Other Infections

Studies on IFNL4 variants and other infectious diseases have yielded mixed results. Infection with certain members of the herpesvirus family (herpesviridae) is very common in humans, resulting in a latent infection that can cause disease upon reactivation. For example, infection with a herpes simplex virus (HSV) may manifest in the form of herpes labialis (cold sores) or genital herpes. In a European population, individuals who carry the IFNL4 rs12979860-T allele (and therefore generate IFNL4 protein) were found to have more episodes of severe herpes labialis (Griffiths et al., 2013). However, in a large cohort of HIV-infected women, genotype for the IFNL4-ΔG/TT polymorphism was not associated with HSV-related outcomes, including episodes of oral or genital herpes (Lang Kuhs et al., 2015). Human cytomegalovirus (human betaherpesvirus 5) infection can be reactivated in patients who become immunocompromised after organ transplantation or due to advanced HIV infection. Homozygosity for IFNL4-ΔG has been linked to increased risk for cytomegalovirus retinitis in HIV patients (S. Bibert et al., 2014). Additionally, the IFNL4-ΔG allele has been associated with both higher rates of cytomegalovirus replication and more symptoms due to cytomegalovirus infection in both solid-organ (Manuel et al., 2015) and stem cell transplant patients (Annibali et al., 2018).

5. Biological Functions

Interferon lambda proteins use the IFNLR1 and IL10R2 receptors for signaling and, on that basis, are classified as type-III interferons. Signaling initiated by IFN-λ or IFN-α triggers the JAK-STAT pathway, leading to the expression of numerous interferon-stimulated genes with anti-viral and anti-proliferative effects. In contrast to the ubiquitous expression of receptors for IFN-α, IFNLR1 is largely restricted to tissues of epithelial origin (Kotenko et al., 2003; Sheppard et al., 2003), therefore, interferon lambda proteins may have evolved specifically to protect the epithelium. In vitro studies have revealed that interferon-stimulated gene expression and anti-viral activity induced by recombinant IFNL4 are comparable to that induced by IFNL3 (Hamming et al., 2013), however, the antiviral effects of IFNL4 have faster onset than those produced by other members of the interferon lambda family (Obajemu et al., 2017).

Given that interferons are generally considered to be antiviral cytokines and that IFNL4 has demonstrated anti-viral properties, the observed association between the IFNL4-ΔG allele, which generates the IFNL4 protein, and impaired clearance of HCV seems paradoxical (O’Brien et al., 2014). The explanation for this paradox is not apparent and IFNL4 variant associations with hepatic inflammation and fibrosis, opportunistic viral infections, and cancers only raise further questions.

Higher interferon stimulated gene expression associated with IFNL4 indicate that this protein does have in vivo antiviral effects, but, at least for HCV infection, other manifestations seem to override those influences (Onabajo, Muchmore, & Prokunina-Olsson, 2019). While most interferon stimulated genes have antiviral effects, some may enhance viral replication (Schoggins & Rice, 2011). IFNL4 induces expression of USP18 and ISG15, (Wong & Chen, 2016) which interfere with the function of IFN-α (Sung et al., 2017), although it is not clear that this occurs in vivo during HCV infection (Onabajo et al., 2019). SOCS1, another negative regulator of the immune response to viral infections, may also be induced by IFNL4 (Obajemu et al., 2017). It is possible that IFNL4 interferes with the antiviral activity of other interferons. There is evidence that IFNL4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of negative regulators of the interferon response and that IFNL4 acts faster than other type III IFNs in inducing such genes (Fan et al., 2016; Obajemu et al., 2017; Onabajo et al., 2019).

6. Conclusions and Future Directions

Since the initiation of the GWAS design over 15 years ago, investigators have conducted more than 4,000 such studies in a wide range of diseases (Buniello et al., 2019). These efforts have yielded many associations with SNP markers, yet relatively few novel biological insights. The discoveries of the IFNL4 gene and IFNL4-ΔG/TT (rs368234815) variant as a result of GWAS of HCV clearance provide an exception to that record. In addition to identifying a new gene, this work has led to new insights into interferon biology by providing evidence that an interferon protein may impair rather than enhance viral clearance.

These discoveries have translational potential. Prior to the discovery of IFNL4, genotype for the rs12979860 SNP was used to predict response of HCV-infected patients to treatment with pegylated interferon-α/ribavirin therapy. Newer regimens based on combinations of DAAs are much more effective than pegylated interferon-α/ribavirin and testing for IFNL4 genotype is not currently recommended for those regimens. However, DAA regimens remain expensive and use of IFNL4 genotype to predict response to shorter than standard duration treatment could be cost effective either by personalizing the duration of treatment for individual patients or employing a shorter duration of treatment as the standard of care in populations, such as East Asians, that have a high frequency of the IFNL4-TT/TT genotype (O’Brien, Kottilil, & Pfeiffer, 2017). Theoretically, IFNL4 genotype might be used to customize treatment of acute HCV infection, however, in that setting it might be impracticable to obtain IFNL4 genotype results quickly enough to inform clinical decisions.

Recent studies, primarily in mouse models, have demonstrated that other members of the interferon lambda family provide tissue barrier protection against a wide range of viral pathogens, including neuroinvasive West Nile virus infection (Lazear et al., 2015), respiratory infections including influenza (Crotta et al., 2013; Galani et al., 2017; Klinkhammer et al., 2018) and gastrointestinal viruses such as norovirus (Nice et al., 2015) and rotavirus (Hernandez et al., 2015). Given the strong evolutionary selection against the IFNL4 protein-generating IFNL4-ΔG allele, genotype for the IFNL4-ΔG/TT variant may play an important role in other infectious diseases, therefore, future epidemiological studies should examine those relationships.

Interferons are generally considered to be anti-viral cytokines that are generated in response to viral invasion. Results from studies of IFNL4 variants challenge that paradigm. The IFNL4 protein has anti-viral properties in vitro, however, individuals who are homozygous for the IFNL4-TT allele and do not generate this protein, are more likely to clear infection with HCV. Nonalcoholic fatty liver disease is not caused by a viral infection; therefore, this condition would not be expected to induce expression of interferons, yet in patients with this condition, IFNL4 genotype affects the development of hepatic inflammation and fibrosis. Future research aimed at understanding these paradoxes may further our understanding of interferon biology.

Highlights.

  • Interferon lambda 4 (IFNL4) is a recently discovered human gene

  • Common variant IFNL4-ΔG/TT (rs368234815) controls generation of IFNL4 protein

  • There has been strong selection for the IFNL4-TT allele, which abrogates IFNL4

  • IFNL4-ΔG/TT plays a key role in clearance of hepatitis C virus infection

  • IFNL4-ΔG/TT genotype has also been associated with several other phenotypes

7. Acknowledgements

This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series--a series resulting from collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by the National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE.

The corresponding Gene Wiki entry for this review can be found here: https://en.wikipedia.org/wiki/IFNL4

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Abbreviations

GWAS

Genome-Wide Association Study

HCV

Hepatitis C Virus

IFN

Interferon

IL

Interleukin

SNP

Single Nucleotide Polymorphism

SVR

Sustained Viral Response

Footnotes

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Competing Financial Interests: TRO’B is a coinventor on a patent for the IFN-λ4 protein held by the National Cancer Institute.

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