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Multi-ancestry genome-wide association study of spontaneous clearance of hepatitis C virus

Multi-ancestry genome-wide association study of spontaneous clearance of hepatitis C virus
Multi-ancestry genome-wide association study of spontaneous clearance of hepatitis C virus
Background & Aims: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. Methods: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina arrays and statistically imputed to 1000 Genomes Project. For each ancestry group, the association of single nucleotide polymorphisms with HCV clearance was tested by log-additive analysis and then a meta-analysis was performed. Results: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4–IFNL3 (19q13.2; P=5.99x10–50) and the MHC locus 6p21.32 (P=1.15x10–21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P=1.80x10–07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared to individuals carrying none or 1 of the clearance-associated variants. Conclusions: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4–IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.
0016-5085
1496-1507.e7
Vergara, Candelaria
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Thio, Chloe L.
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Johnson, Eric
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Kral, Alex H.
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O’brien, Thomas R.
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Goedert, James J.
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Mangia, Alessandra
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Piazzolla, Valeria
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Mehta, Shruti H.
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Kirk, Gregory D.
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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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Cox, Andrea L.
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Peters, Marion G.
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Khakoo, Salim I.
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Alric, Laurent
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Cramp, Matthew E.
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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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Rosen, Hugo R.
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Murphy, Edward L.
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Latanich, Rachel
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Wojcik, Genevieve L.
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Taub, Margaret A.
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Valencia, Ana
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Thomas, David L.
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Duggal, Priya
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Vergara, Candelaria
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Thio, Chloe L.
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Johnson, Eric
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Kral, Alex H.
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O’brien, Thomas R.
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Goedert, James J.
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Mangia, Alessandra
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Piazzolla, Valeria
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Mehta, Shruti H.
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Kirk, Gregory D.
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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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Cox, Andrea L.
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Peters, Marion G.
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Khakoo, Salim I.
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Alric, Laurent
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Cramp, Matthew E.
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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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Rosen, Hugo R.
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Murphy, Edward L.
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Latanich, Rachel
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Wojcik, Genevieve L.
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Taub, Margaret A.
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Valencia, Ana
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Thomas, David L.
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Duggal, Priya
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Vergara, Candelaria, Thio, Chloe L., Johnson, Eric, Kral, Alex H., O’brien, Thomas R., Goedert, James J., Mangia, Alessandra, Piazzolla, Valeria, Mehta, Shruti H., Kirk, Gregory D., Kim, Arthur Y., Lauer, Georg M., Chung, Raymond T., Cox, Andrea L., Peters, Marion G., Khakoo, Salim I., Alric, Laurent, Cramp, Matthew E., Donfield, Sharyne M., Edlin, Brian R., Busch, Michael P., Alexander, Graeme, Rosen, Hugo R., Murphy, Edward L., Latanich, Rachel, Wojcik, Genevieve L., Taub, Margaret A., Valencia, Ana, Thomas, David L. and Duggal, Priya (2019) Multi-ancestry genome-wide association study of spontaneous clearance of hepatitis C virus. Gastroenterology, 156 (5), 1496-1507.e7. (doi:10.1053/j.gastro.2018.12.014).

Record type: Article

Abstract

Background & Aims: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. Methods: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina arrays and statistically imputed to 1000 Genomes Project. For each ancestry group, the association of single nucleotide polymorphisms with HCV clearance was tested by log-additive analysis and then a meta-analysis was performed. Results: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4–IFNL3 (19q13.2; P=5.99x10–50) and the MHC locus 6p21.32 (P=1.15x10–21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P=1.80x10–07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared to individuals carrying none or 1 of the clearance-associated variants. Conclusions: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4–IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.

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Accepted/In Press date: 19 December 2018
e-pub ahead of print date: 26 December 2018
Published date: April 2019

Identifiers

Local EPrints ID: 427358
URI: http://eprints.soton.ac.uk/id/eprint/427358
ISSN: 0016-5085
PURE UUID: 75b97923-780f-4001-810d-25ae023983c4

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Date deposited: 14 Jan 2019 17:30
Last modified: 07 Oct 2020 05:10

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Contributors

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

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