Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance

Abstract

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 generation of the 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 (r2=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.

Prolonged activation of innate antiviral gene signature after childbirth is determined byIFNL3genotype

“…First, the mechanism by which the IFNL3 rs12979860 SNP exerts an effect on ISG signaling in any cell type is unsettled, with uncertainty about whether the SNP is actually functional or whether its effect is mediated by other IFNL SNPs in high linkage disequilibrium (33). Individuals with a ΔG genotype (vs. T) at the IFNL4 variant rs368234815 express a transcript encoding the IFN-λ4 protein, which has been demonstrated to induce IFN signaling (33,34). All of the NPC subjects and mothers from our study were genotyped at rs368234815, and in each individual there was a direct correlation between IFNL3 SNP rs12979860 and IFNL4 rs368234815 genotypes (Table S1).…”

“…Genotypes of NPC and postpartum subjects at IFNL3 SNP rs12979860 and IFNL4 were determined as described (18,34). Briefly, genomic DNA was isolated from patient samples by using the PureLink Genomic DNA Mini Kit (Qiagen) per the manufacturer's protocol.…”

Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery

“…The rs12979860 SNP itself may not be functional; rather, its effect appears to be mediated by other closely linked IFN-λ polymorphisms, including the IFNL4 ΔG/TT variant rs368234815 (26,27). The ΔG frameshift variant permits production of the novel protein IFN-λ4, which is paradoxically associated with impaired resolution of HCV infection (26,27). In our cohort, the favorable IFNL3 rs12979860 C allele was in 100% linkage disequilibrium with the favorable IFNL4 rs368234815 TT allele (Table S1).…”

“…The mechanism by which polymorphisms at rs12979860 might contribute to control of HCV after pregnancy is not clear. The rs12979860 SNP itself may not be functional; rather, its effect appears to be mediated by other closely linked IFN-λ polymorphisms, including the IFNL4 ΔG/TT variant rs368234815 (26,27). The ΔG frameshift variant permits production of the novel protein IFN-λ4, which is paradoxically associated with impaired resolution of HCV infection (26,27).…”

Gene–disease association with human IFNL locus polymorphisms extends beyond hepatitis C virus infections

“…A recent report compared the strength of association of rs4803217 and rs368234815 in IFN treatment response in HCV-infected African Americans, who have the lowest reported LD values among all ethnicities between rs368234815 and rs12979860 SNPs (Figure 1b). 107 They found that rs368234815 was more strongly associated with the outcome than rs4803217. 107 In another independent report, Lu et al applied multivariate regression to test the independence of rs368234815 from rs4803217 in predicting response to IFN treatment in HCV patients of AfricanAmerican decent.…”