A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus

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

doi:10.1093/infdis/jiaa677

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus

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

^*Corresponding author for this work

Peninsula Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

Abstract Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

Original language	English
Pages (from-to)	2090-2098
Number of pages	0
Journal	The Journal of Infectious Diseases
Volume	223
Issue number	12
Early online date	29 Oct 2020
DOIs	https://doi.org/10.1093/infdis/jiaa677
Publication status	Published - 15 Jun 2021

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Vergara, C., Valencia, A., Thio, C. L., Goedert, J. J., Mangia, A., Piazzolla, V., Johnson, E., Kral, A. H., O’Brien, TR., Mehta, S. H., Kirk, G. D., Kim, A. Y., Lauer, G. M., Chung, R. T., Cox, A. L., Peters, M. G., Khakoo, S. I., Alric, L., Cramp, M. E., ... Duggal, P. (2021). A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus. The Journal of Infectious Diseases, 223(12), 2090-2098. https://doi.org/10.1093/infdis/jiaa677

@article{e9389f0e7c684852b9c6e238e572d2f5,

title = "A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus",

abstract = "Abstract Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development. ",

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

year = "2021",

month = jun,

day = "15",

doi = "10.1093/infdis/jiaa677",

language = "English",

volume = "223",

pages = "2090--2098",

journal = "The Journal of Infectious Diseases",

issn = "0022-1899",

number = "12",

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Vergara, C, Valencia, A, Thio, CL, Goedert, JJ, Mangia, A, Piazzolla, V, Johnson, E, Kral, AH, O’Brien, TR, Mehta, SH, Kirk, GD, Kim, AY, Lauer, GM, Chung, RT, Cox, AL, Peters, MG, Khakoo, SI, Alric, L, Cramp, ME, Donfield, SM, Edlin, BR, Busch, MP, Alexander, G, Rosen, HR, Murphy, EL, Wojcik, GL, Taub, MA, Thomas, DL & Duggal, P 2021, 'A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus', The Journal of Infectious Diseases, vol. 223, no. 12, pp. 2090-2098. https://doi.org/10.1093/infdis/jiaa677

TY - JOUR

T1 - A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus

AU - Vergara, Candelaria

AU - Valencia, Ana

AU - Thio, Chloe L.

AU - Goedert, James J.

AU - Mangia, Alessandra

AU - Piazzolla, Valeria

AU - Johnson, Eric

AU - Kral, Alex H.

AU - O’Brien, TR

AU - Mehta, Shruti H.

AU - Kirk, Gregory D.

AU - Kim, Arthur Y.

AU - Lauer, Georg M.

AU - Chung, Raymond T.

AU - Cox, Andrea L.

AU - Peters, Marion G.

AU - Khakoo, Salim I.

AU - Alric, Laurent

AU - Cramp, Matthew E.

AU - Donfield, Sharyne M.

AU - Edlin, Brian R.

AU - Busch, Michael P.

AU - Alexander, Graeme

AU - Rosen, Hugo R.

AU - Murphy, Edward L.

AU - Wojcik, Genevieve L.

AU - Taub, Margaret A.

AU - Thomas, David L.

AU - Duggal, Priya

PY - 2021/6/15

Y1 - 2021/6/15

N2 - Abstract Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

AB - Abstract Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

U2 - 10.1093/infdis/jiaa677

DO - 10.1093/infdis/jiaa677

M3 - Article

SN - 0022-1899

VL - 223

SP - 2090

EP - 2098

JO - The Journal of Infectious Diseases

JF - The Journal of Infectious Diseases

IS - 12

ER -

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus

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