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. Murphy; Arthur 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

doi:10.1038/s41435-020-00115-3

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 journal › Article › peer-review

2 Scopus citations

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 language	English (US)
Pages (from-to)	348-359
Number of pages	12
Journal	Genes and immunity
Volume	21
Issue number	5
DOIs	https://doi.org/10.1038/s41435-020-00115-3
State	Published - Nov 2020

ASJC Scopus subject areas

Immunology
Genetics
Genetics(clinical)

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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

Vergara, C , Duggal, P , Thio, CL, Valencia, A, Brien, TRO, Latanich, R, Timp, W, Johnson, EO, Kral, AH, Mangia, A, Goedert, JJ, Piazzola, V, Mehta, SH , Kirk, GD, Peters, MG, Donfield, SM, Edlin, BR, Busch, MP, Alexander, G, Murphy, EL, Kim, AY, Lauer, GM, Chung, RT, Cramp, ME, Cox, AL, Khakoo, SI, Rosen, HR, Alric, L, Wheelan, SJ, Wojcik, GL , Thomas, DL & Taub, MA 2020, 'Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection', Genes and immunity, vol. 21, no. 5, pp. 348-359. https://doi.org/10.1038/s41435-020-00115-3

@article{26901ef5c4e24c628296e7c44c72576a,

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

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.",

author = "Candelaria Vergara and Priya Duggal and Thio, {Chloe L.} and Ana Valencia and Brien, {Thomas R.O{\textquoteright}} and Rachel Latanich and Winston Timp and Johnson, {Eric O.} and Kral, {Alex H.} and Alessandra Mangia and Goedert, {James J.} and Valeria Piazzola and Mehta, {Shruti H.} and Kirk, {Gregory D.} and Peters, {Marion G.} and Donfield, {Sharyne M.} and Edlin, {Brian R.} and Busch, {Michael P.} and Graeme Alexander and Murphy, {Edward L.} and Kim, {Arthur Y.} and Lauer, {Georg M.} and Chung, {Raymond T.} and Cramp, {Matthew E.} and Cox, {Andrea L.} and Khakoo, {Salim I.} and Rosen, {Hugo R.} and Laurent Alric and Wheelan, {Sarah J.} and Wojcik, {Genevieve L.} and Thomas, {David L.} and Taub, {Margaret A.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = nov,

doi = "10.1038/s41435-020-00115-3",

language = "English (US)",

volume = "21",

pages = "348--359",

journal = "Genes and immunity",

issn = "1466-4879",

publisher = "Nature Publishing Group",

number = "5",

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TY - JOUR

T1 - Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection

AU - Vergara, Candelaria

AU - Duggal, Priya

AU - Thio, Chloe L.

AU - Valencia, Ana

AU - Brien, Thomas R.O’

AU - Latanich, Rachel

AU - Timp, Winston

AU - Johnson, Eric O.

AU - Kral, Alex H.

AU - Mangia, Alessandra

AU - Goedert, James J.

AU - Piazzola, Valeria

AU - Mehta, Shruti H.

AU - Kirk, Gregory D.

AU - Peters, Marion G.

AU - Donfield, Sharyne M.

AU - Edlin, Brian R.

AU - Busch, Michael P.

AU - Alexander, Graeme

AU - Murphy, Edward L.

AU - Kim, Arthur Y.

AU - Lauer, Georg M.

AU - Chung, Raymond T.

AU - Cramp, Matthew E.

AU - Cox, Andrea L.

AU - Khakoo, Salim I.

AU - Rosen, Hugo R.

AU - Alric, Laurent

AU - Wheelan, Sarah J.

AU - Wojcik, Genevieve L.

AU - Thomas, David L.

AU - Taub, Margaret A.

PY - 2020/11

Y1 - 2020/11

N2 - 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.

AB - 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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SP - 348

EP - 359

JO - Genes and immunity

JF - Genes and immunity

IS - 5

ER -

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

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