Candelaria Vergara1, Ana Valencia2,3, Chloe L Thio2, James J Goedert4, Alessandra Mangia5, Valeria Piazzolla5, Eric Johnson6, Alex H Kral6, Thomas R O'Brien4, Shruti H Mehta1, Gregory D Kirk1,2, Arthur Y Kim7, Georg M Lauer8, Raymond T Chung8, Andrea L Cox1, Marion G Peters9, Salim I Khakoo10, Laurent Alric11, Matthew E Cramp12, Sharyne M Donfield13, Brian R Edlin14, Michael P Busch15, Graeme Alexander16, Hugo R Rosen17, Edward L Murphy15, Genevieve L Wojcik1, Margaret A Taub1, David L Thomas2, Priya Duggal2. 1. Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA. 2. Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA. 3. Universidad Pontificia Bolivariana, Medellín, Colombia. 4. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 5. Liver Unit IRCCS "Casa Sollievo della Sofferenza," San Giovanni Rotondo, Italy. 6. RTI International, Research Triangle Park, North Carolina, USA. 7. Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 8. Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. 9. Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Francisco, California, USA. 10. University of Southampton, Southampton General Hospital, Southampton, United Kingdom. 11. Department of Internal Medicine and Digestive Diseases, CHU Rangueil, UMR 152 IRD, Toulouse 3 University, France. 12. South West Liver Unit, Plymouth, United Kingdom. 13. Rho, Inc., Chapel Hill, North Carolina, USA. 14. SUNY Downstate College of Medicine, Brooklyn, New York, USA. 15. University of California and Vitalant Research Institute, San Francisco, California, USA. 16. UCL Institute for Liver and Digestive Health, Royal Free Hospital, Hampstead, London, United Kingdom. 17. University of Colorado, Aurora, Colorado, USA.
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.
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.
Authors: Rafal S Sobota; Daniel Shriner; Nuri Kodaman; Robert Goodloe; Wei Zheng; Yu-Tang Gao; Todd L Edwards; Christopher I Amos; Scott M Williams Journal: Ann Hum Genet Date: 2015-01-22 Impact factor: 1.670
Authors: Christopher C Chang; Carson C Chow; Laurent Cam Tellier; Shashaank Vattikuti; Shaun M Purcell; James J Lee Journal: Gigascience Date: 2015-02-25 Impact factor: 6.524