Multi-ancestry Fine Mapping of Interferon Lambda and the Outcome of Acute Hepatitis C Virus Infection

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV-clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N=16) and ΔG/persistent (N=15) (genotype-outcome concordant) or TT/persistent (N=19) and ΔG/clearance (N=14) (discordant). 25 SNPs had a difference in counts of alternative allele > 5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P=4.9×10(−04)) and rs8099917 (P=5.5×10(−04)). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7x more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P=3.6×10(−05)). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV-clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P=1.8×10(−04)). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.