- Vergara, Candelaria;
- Duggal, Priya;
- Thio, Chloe L;
- Valencia, Ana;
- O’Brien, Thomas R;
- Latanich, Rachel;
- Timp, Winston;
- Johnson, Eric O;
- Kral, Alex H;
- Mangia, Alessandra;
- Goedert, James J;
- Piazzola, Valeria;
- Mehta, Shruti H;
- Kirk, Gregory D;
- Peters, Marion G;
- Donfield, Sharyne M;
- Edlin, Brian R;
- Busch, Michael P;
- Alexander, Graeme;
- Murphy, Edward L;
- Kim, Arthur Y;
- Lauer, Georg M;
- Chung, Raymond T;
- Cramp, Matthew E;
- Cox, Andrea L;
- Khakoo, Salim I;
- Rosen, Hugo R;
- Alric, Laurent;
- Wheelan, Sarah J;
- Wojcik, Genevieve L;
- Thomas, David L;
- Taub, Margaret A
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 value = 4.9 × 10-04) and rs8099917 (P value = 5.5 × 10-04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 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 value = 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.