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

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

1466-4879
348-359
Vergara, Candelaria
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Duggal, Priya
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Thio, Chloe L.
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Valencia, Ana
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Brien, Thomas R.O’
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Latanich, Rachel
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Timp, Winston
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Johnson, Eric O.
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Kral, Alex H.
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Mangia, Alessandra
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Goedert, James J.
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Piazzola, Valeria
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Mehta, Shruti H.
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Kirk, Gregory D.
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Peters, Marion G.
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Donfield, Sharyne M.
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Edlin, Brian R.
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Busch, Michael P.
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Alexander, Graeme
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Murphy, Edward L.
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Kim, Arthur Y.
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Lauer, Georg M.
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Chung, Raymond T.
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Cramp, Matthew E.
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Cox, Andrea L.
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Khakoo, Salim I.
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Rosen, Hugo R.
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Alric, Laurent
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Wheelan, Sarah J.
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Wojcik, Genevieve L.
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Taub, Margaret A.
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Vergara, Candelaria
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Duggal, Priya
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Thio, Chloe L.
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Valencia, Ana
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Brien, Thomas R.O’
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Latanich, Rachel
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Timp, Winston
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Johnson, Eric O.
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Kral, Alex H.
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Mangia, Alessandra
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Goedert, James J.
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Piazzola, Valeria
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Mehta, Shruti H.
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Kirk, Gregory D.
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Peters, Marion G.
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Donfield, Sharyne M.
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Edlin, Brian R.
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Busch, Michael P.
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Alexander, Graeme
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Murphy, Edward L.
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Kim, Arthur Y.
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Lauer, Georg M.
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Chung, Raymond T.
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Cramp, Matthew E.
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Cox, Andrea L.
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Khakoo, Salim I.
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Rosen, Hugo R.
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Alric, Laurent
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Wheelan, Sarah J.
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Wojcik, Genevieve L.
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Thomas, David L.
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Taub, Margaret A.
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Vergara, Candelaria, Duggal, Priya, Thio, Chloe L., Valencia, Ana, Brien, Thomas R.O’, 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. and Taub, Margaret 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. (doi:10.1038/s41435-020-00115-3).

Record type: Article

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.

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More information

Accepted/In Press date: 12 October 2020
e-pub ahead of print date: 28 October 2020
Published date: November 2020

Identifiers

Local EPrints ID: 445362
URI: http://eprints.soton.ac.uk/id/eprint/445362
ISSN: 1466-4879
PURE UUID: 668a4a78-43b2-4f89-82ba-7cb179fc93ce

Catalogue record

Date deposited: 04 Dec 2020 17:30
Last modified: 26 Nov 2021 06:38

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Contributors

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

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