Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQβ1 |
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| Institution: | 1. Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA;2. Universidad Pontificia Bolivariana, Medellín, Antioquia 050031, Colombia;3. Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA;4. Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes 44000, France;5. Center for infectious Diseases and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA;6. GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, NC 27709, USA;7. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;8. Liver Unit, Medical Sciences Department, Fondazione “Casa Sollievo della Sofferenza” IRCCS, 71013 San Giovanni Rotondo, Italy;9. Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;10. Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;11. Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Francisco, CA 94143, USA;12. University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK;13. Internal Medicine-Department of Digestive Diseases, Rangueil Hospital, Toulouse University, 1, 31400 Toulouse, France;14. South West Liver Unit, Plymouth PL6 8DH, UK;15. Rho, Inc., Durham, NC 27713, USA;16. SUNY Downstate College of Medicine, Brooklyn, NY 11203, USA;17. University of California San Francisco and Vitalant Research Institute, San Francisco, CA 94118, USA;18. UCL Institute for Liver and Digestive Health, The Royal Free Hospital, Pond St, Hampstead, London NW3 2QG, UK;19. University of Colorado, Aurora, CO 80045, USA;20. Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;21. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;22. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA;23. Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92093, USA |
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| Abstract: | Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p valueMeta = 1.24 × 10?14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p valueMeta = 8.23 × 10?11) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1103:01, and HLA-DRB1101:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10?38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection. |
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| Keywords: | hepatitis C virus fine-mapping HLA-DQβ1 HCV clearance trans-ancestral host genetics MHC GWAS HLA imputation infection |
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