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The discovery that genetic variation within the interferon lambda locus has a profound effect on the outcome of hepatitis C virus (HCV) treatment and spontaneous clearance of HCV is one of the great triumphs of genomic medicine. Subsequently, the IFNL4 gene was discovered and proposed as the causal gene underlying this association. However, there has been a lively debate within the field concerning the causality, which has been further complicated by a change in naming. This review summarizes the genetic data available for the IFNL3/IFNl4 loci and provides an in-depth discussion of causality. We also discuss a new series of interesting data suggesting that the genetic variation at the IFNL4 loci influences the evolution of the HCV virus and the implication this relationship between our genetic makeup and virus evolution has upon our understanding of the IFNL4 system. Finally, new data support an influence of the IFNL4 gene upon liver inflammation and fibrosis that is independent of etiology, thereby linking the IFNL4 gene to some of the major liver diseases of today., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8 + T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8 + T cell responses of these patients.

IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor ( VLDLR ), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells., Competing Interests: TO’B and LP-O are co-inventors on IFN-λ4-related patents issued to NCI/NIH and receive royalties for antibodies for IFN-λ4 detection. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Onabajo, Wang, Lee, Florez-Vargas, Obajemu, Tanikawa, Vargas, Liao, Song, Huang, Shen, Banday, O’Brien, Hu, Matsuda and Prokunina-Olsson.)

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 diseases. 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., (Published by Elsevier B.V.)

Background: Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown., Methods: We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype., Results: The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status., Conclusions: Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In 2009, genome-wide association studies (GWAS) strongly linked genetic variants in the interferon lambda (IFN-λ) chromosomal region to HCV clearance. In 2013, discovery of the IFNL4 gene provided a functional explanation for those GWAS findings. The IFNL4- ΔG/TT (rs368234815) variant controls generation of the IFN-λ4 protein. Paradoxically, the IFNL4- TT allele, which abrogates IFN-λ4, associates with higher rates of spontaneous HCV clearance and better response to treatments for HCV infection. The finding that a "knock-out" allele for IFN-λ4 enhances HCV clearance challenges the paradigm of IFNs as antiviral cytokines. Genetic variants in the IFN-λ region have also been associated with hepatic inflammation and fibrosis from various etiologies, however, alleles that are linked with improved HCV clearance associates with worse inflammation and fibrosis. These studies demonstrate that GWAS of infectious diseases may yield important and unexpected biological insights.

In direct acting antiviral (DAA)-treated HCV genotype 1, the sustained virologic response rate with the ∆G/∆G genotype of IFNL4 rs368234815 (86.8%) was significantly lower than with ∆G/TT (95.9%, P = 0.03) or TT/TT (98.6%, P = 0.01). The SVR odds ratio for ∆G/∆G compared to TT/TT was 0.10 (P = 0.03). IFNL4 genotype might predict DAA-response., (Published by Elsevier Inc.)

Background & Aims: Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability., Methods: We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach., Results: Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048)., Conclusion: IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance., (Published by Elsevier B.V.)

IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women's Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)-infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV-1 and HSV-2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV-2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV-1 and 79.0% were positive for HSV-2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV-1 or HSV-2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV-2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV-2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.

Interferons (IFNs) are generally considered antiviral cytokines, yet the newly discovered IFN-λ4 is linked with the failure to clear hepatitis C virus (HCV) infection either spontaneously or in response to treatment. IFN-λ4 can be generated only by individuals who carry the IFNL4-ΔG allele (rs368234815), which is the strongest known host factor for predicting clearance of HCV. The ancestral IFNL4-ΔG allele is the major variant in Africans while the minor variant in Asians, suggesting very strong negative genetic selection for this allele-most likely driven by an infectious agent other than HCV. IFN-λ4 most closely resembles IFN-λ3, but these proteins share only 29% amino-acid identity, and, in contrast to IFN-λ3, IFN-λ4 is only weakly secreted. Nevertheless, IFN-λ4 signals through the IFN-λ receptor complex and induces expression of IFN-stimulated genes via the Janus kinase-signal transducer and activator of transcription signaling pathway. Although the IFNL4-ΔG variant is strongly associated with the failure to clear HCV infection, HCV-infected patients who carry this allele have lower baseline HCV RNA levels in the absence of treatment. Resolving the paradoxical functions of IFN-λ4, which appears to induce antiviral activity yet impair effective clearance of HCV, may yield critical new insights into the immunologic response to HCV infection and IFN biology.

Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-α-free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-ΔG is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-λ4 in IFN-α-free DAA therapies.

Interferon lambda 4 protein can be generated in IFNL4-ΔG carriers but not IFNL4-TT homozygotes. We studied 890 anti-hepatitis C virus (HCV)-positive participants in the Women's Interagency HIV Study. Among blacks (n = 555), HCV was more often cleared for those with genotype IFNL4-TT/TT (32.6%; odds ratio [OR], 3.59; P = 3.3 × 10(-5)) than IFNL4-TT/ΔG (11.3%; OR, 0.95; P = .86) or IFNL4-ΔG/ΔG (11.9%; referent). Pooling these data with published results in blacks (n = 1678), ORs were 3.84 (P = 8.6 × 10(-14)) for IFNL4-TT/TT and 1.44 (P = .03) IFNL4-TT/ΔG, and the area under the curve was 0.64 for IFNL4-ΔG genotype and 0.61 for rs12979860 (IL28B). IFNL4-ΔG is strongly associated with impaired spontaneous HCV clearance.

Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

Unlabelled: In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV enzyme immunoassay were tested for HCV viremia by a branched-chain DNA assay. HCV genotype was determined by sequencing the HCV nonstructural 5B protein region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1,701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). Human immunodeficiency virus type 1 (HIV-1) prevalence was 13.9%. The overall median HCV RNA level was 6.45 log(10) copies/mL. In unadjusted analyses, higher levels were found with older age, male gender, African-American ancestry, hepatitis B virus infection, HIV-1 infection, and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotypes 3 or 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype, and IL28B rs12979860 genotype were all independently associated with HCV RNA., Conclusion: The level of HCV viremia is influenced by a large number of demographic, viral, and human genetic factors., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Among 1369 Urban Health Study participants, we evaluated genetic models for the association of IL28B genotype (rs12979860 and rs8099917) with hepatitis C virus (HCV) clearance. For rs12979860, adjusted odds ratios for spontaneous HCV clearance were as follows: IL28B-CC, 3.88 (P < .001); IL28B-CT, 1.48 (P = .08). On the basis of Akaike information criteria values and χ(2) tests, a supra-additive (quadratic) model fit these data best. Models based on rs8099917 provided poorer fit. Evidence that a supra-additive rs12979860-based model best fits the association of IL28B-genotype with HCV clearance may improve clinical prediction models and foster a better understanding of functional mechanisms underlying this association.

Interferon (IFN)-α, a type-I IFN, is widely used to treat chronic hepatitis C virus infection, but the broad expression of IFN-α receptors often leads to adverse reactions in many organs. Here, we examine IFN-λ, a type-III IFN, as a therapeutic alternative to IFN-α. Like IFN-α, IFN-λ also induces antiviral activity in hepatocytes, but might induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virological response to therapy with pegylated IFN-α plus ribavirin in patients with chronic hepatitis C., (Published by Elsevier Ltd.)

Background: Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables., Methods: HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC)., Results: Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study., Conclusion: A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.

BackgroundIFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers.MethodsWe examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies.ResultsWe found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count.ConclusionsThe absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Background & aimsSpontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry.MethodsWe performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed.ResultsIn the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants.ConclusionsIn a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.

Background & aimsGenetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability.MethodsWe compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach.ResultsAmong European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048).ConclusionIFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.