ID: 89: Comparison of IFNL4-ΔG/TT and IFNL3 rs4803217 for association with hepatitis C virus clearance

Genetic polymorphisms within the interferon lambda region are strongly associated with hepatitis C virus (HCV) clearance; the rs368234815 (IFNL4- Δ G/TT) polymorphism, which controls generation of the IFNL4 protein, is more strongly associated with HCV clearance than rs12979860 (the ‘IL28B marker’). A polymorphism rs4803217 within the 3’ untranslated region of IFNL3 has been proposed as a causal variant affecting HCV clearance by altering IFNL3 mRNA stability. We compared response to peg-IFN- α /ribavirin treatment in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS sets in relation to genotypes and haplotypes of rs368234815 and rs4803217. In European Americans, linkage disequilibrium between rs368234815 and rs4803217 was strong ( r 2  = 0.89–0.99) and there were no significant differences between the variants. Decreased linkage disequilibrium between these variants in African Americans ( r 2  = 0.74–0.80), allowed comparisons between these candidates. In individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with rs368234815 than rs4803217 ( p  = 0.003); the rs368234815-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response ( p  = 0.03, compared to rs368234815-ΔG:rs4803217-T haplotype). Associations with 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) were also stronger for rs368234815 than rs4803217. Our results provide evidence that rs3682348150 is associated with HCV clearance stronger than rs4803217 and suggest a possible negative role for the IFNL3 rs4803217-G allele in individuals who can produce IFNL4 protein.