Lesley-Ann Gray1,2, Heather A D'Antoine3, Steven Y C Tong3,4, Melita McKinnon3, Dawn Bessarab5, Ngiare Brown6, Bo Reményi3, Andrew Steer7,8, Genevieve Syn9, Jenefer M Blackwell9, Michael Inouye1,2, Jonathan R Carapetis3,9. 1. School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia. 2. Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. 3. Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. 4. Victorian Infectious Disease Service, The Royal Melbourne Hospital and Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Victoria, Australia. 5. Centre for Aboriginal Medical and Dental Health, The University of Western Australia, Crawley, Western Australia. 6. School of Education, The University of Wollongong, New South Wales, Australia. 7. Group A Streptococcal Research Group, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. 8. Centre for International Child Health, Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia. 9. Telethon Kids Institute, The University of Western Australia, Roberts Road, Subiaco, Western Australia.
Abstract
Background: Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Methods: Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results: The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09-1.90; P = 9.56 × 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 × 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 × 10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Conclusions: Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.
Background: Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Methods: Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results: The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09-1.90; P = 9.56 × 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 × 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 × 10-3) was protective. Humanmyosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Conclusions: Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis.
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Authors: Jenefer M Blackwell; Timo Lassmann; Alexia L Weeks; Heather A D'Antoine; Melita McKinnon; Genevieve Syn; Dawn Bessarab; Ngiare Brown; Steven Y C Tong; Bo Reményi; Andrew Steer; Lesley-Ann Gray; Michael Inouye; Jonathan R Carapetis Journal: Sci Data Date: 2020-04-29 Impact factor: 6.444
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