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Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection
Vergara, C., Duggal, P., Thio, C. L., Valencia, A., Brien, T. R. O., Latanich, R., Timp, W., Johnson, E. O., Kral, A. H., Mangia, A., Goedert, J. J., Piazzola, V., Mehta, S. H., Kirk, G. D., Peters, M. G., Donfield, S. M., Edlin, B. R., Busch, M. P., Alexander, G., ... Taub, M. A. (2020). Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection. Genes and Immunity, 21(5), 348-359. https://doi.org/10.1038/s41435-020-00115-3
Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/Delta G) 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 Delta G/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and Delta G/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 x 10(-04)) and rs8099917 (P value = 5.5 x 10(-04)). In the European ancestry group, individuals with the haplotype rs368234815 Delta G/rs4803221C were 1.7x more likely to clear than those with the rs368234815 Delta G/rs4803221G haplotype (P value = 3.6 x 10(-05)). For another nearby SNP, the haplotype of rs368234815 Delta G/rs8099917T was associated with HCV clearance compared to rs368234815 Delta G/rs8099917G (OR: 1.6, P value = 1.8 x 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.
