Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection

Candelaria Vergara, Priya Duggal, Chloe L. Thio, Ana Valencia, Thomas R.O’ Brien, Rachel Latanich, Winston Timp, Eric O. Johnson, Alex H. Kral, Alessandra Mangia, James J. Goedert, Valeria Piazzola, Shruti H. Mehta, Gregory D. Kirk, Marion G. Peters, Sharyne M. Donfield, Brian R. Edlin, Michael P. Busch, Graeme Alexander, Edward L. MurphyArthur Y. Kim, Georg M. Lauer, Raymond T. Chung, Matthew E. Cramp, Andrea L. Cox, Salim I. Khakoo, Hugo R. Rosen, Laurent Alric, Sarah J. Wheelan, Genevieve L. Wojcik, David L. Thomas, Margaret A. Taub

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)348-359
Number of pages12
JournalGenes and immunity
Volume21
Issue number5
DOIs
StatePublished - Nov 2020

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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