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, Thomas R. 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

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    Resumen

    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.

    Idioma originalInglés
    Páginas (desde-hasta)2090-2098
    Número de páginas9
    PublicaciónJournal of Infectious Diseases
    Volumen223
    N.º12
    DOI
    EstadoPublicada - 15 jun. 2021

    Nota bibliográfica

    Publisher Copyright:
    © 2020 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

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