1. A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus
- Author
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Vergara, Candelaria, Valencia, Ana, Thio, Chloe L, Goedert, James J, Mangia, Alessandra, Piazzolla, Valeria, Johnson, Eric, Kral, Alex H, O’Brien, Thomas R, 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, Wojcik, Genevieve L, Taub, Margaret A, Thomas, David L, and Duggal, Priya
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Human Genome ,Vaccine Related ,Hepatitis ,Liver Disease ,Women's Health ,Emerging Infectious Diseases ,Prevention ,Infectious Diseases ,Digestive Diseases ,Chronic Liver Disease and Cirrhosis ,Biotechnology ,Immunization ,Hepatitis - C ,Aetiology ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Infection ,Good Health and Well Being ,Female ,Genome-Wide Association Study ,Hepacivirus ,Hepatitis C ,Humans ,Male ,Polymorphism ,Single Nucleotide ,Ribosomal Proteins ,Septins ,Sex Factors ,Viral Load ,HCV ,GWAS ,Sex ,X chromosome ,ARL5B ,Septin 6 ,Host-genetics ,infection ,immune ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundSpontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors.MethodsTo 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.ResultsA 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.ConclusionsThese novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.
- Published
- 2021