PMID- 29029143 OWN - NLM STAT- MEDLINE DCOM- 20171220 LR - 20190210 IS - 1537-6613 (Electronic) IS - 0022-1899 (Linking) VI - 216 IP - 11 DP - 2017 Dec 12 TI - Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry. PG - 1460-1470 LID - 10.1093/infdis/jix497 [doi] AB - 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 x 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 x 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 x 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 x 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. CI - (c) The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. FAU - Gray, Lesley-Ann AU - Gray LA AD - School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia. AD - Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. FAU - D'Antoine, Heather A AU - D'Antoine HA AD - Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. FAU - Tong, Steven Y C AU - Tong SYC AD - Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. AD - Victorian Infectious Disease Service, The Royal Melbourne Hospital and Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Victoria, Australia. FAU - McKinnon, Melita AU - McKinnon M AD - Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. FAU - Bessarab, Dawn AU - Bessarab D AD - Centre for Aboriginal Medical and Dental Health, The University of Western Australia, Crawley, Western Australia. FAU - Brown, Ngiare AU - Brown N AD - School of Education, The University of Wollongong, New South Wales, Australia. FAU - Remenyi, Bo AU - Remenyi B AD - Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. FAU - Steer, Andrew AU - Steer A AD - Group A Streptococcal Research Group, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia. AD - Centre for International Child Health, Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia. FAU - Syn, Genevieve AU - Syn G AD - Telethon Kids Institute, The University of Western Australia, Roberts Road, Subiaco, Western Australia. FAU - Blackwell, Jenefer M AU - Blackwell JM AD - Telethon Kids Institute, The University of Western Australia, Roberts Road, Subiaco, Western Australia. FAU - Inouye, Michael AU - Inouye M AD - School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia. AD - Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. FAU - Carapetis, Jonathan R AU - Carapetis JR AD - Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. AD - Telethon Kids Institute, The University of Western Australia, Roberts Road, Subiaco, Western Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Infect Dis JT - The Journal of infectious diseases JID - 0413675 RN - 0 (Bacterial Outer Membrane Proteins) RN - 0 (Epitopes) RN - 0 (HLA Antigens) RN - 0 (HLA-DQ Antigens) RN - 0 (HLA-DQ alpha-Chains) RN - 0 (HLA-DQA1 antigen) RN - EC 3.6.4.1 (Myosins) SB - IM MH - Australia MH - Bacterial Outer Membrane Proteins/immunology MH - Cross Reactions/immunology MH - Epitopes/immunology MH - *Genetic Predisposition to Disease MH - *Genome-Wide Association Study MH - Genotype MH - HLA Antigens/*genetics/immunology MH - HLA-DQ Antigens/chemistry/classification/genetics/immunology MH - HLA-DQ alpha-Chains/chemistry/classification/genetics/immunology MH - Haplotypes MH - Humans MH - *Molecular Mimicry MH - Myosins/immunology MH - Odds Ratio MH - Polymorphism, Single Nucleotide/genetics MH - Rheumatic Heart Disease/*genetics/*immunology/microbiology MH - Risk Factors MH - Streptococcal Infections/*genetics/*immunology MH - Streptococcus/pathogenicity OTO - NOTNLM OT - GWAS OT - HLA OT - acute rheumatic fever OT - epitope mapping OT - rheumatic heart disease EDAT- 2017/10/14 06:00 MHDA- 2017/12/21 06:00 CRDT- 2017/10/14 06:00 PHST- 2017/07/26 00:00 [received] PHST- 2017/09/20 00:00 [accepted] PHST- 2017/10/14 06:00 [pubmed] PHST- 2017/12/21 06:00 [medline] PHST- 2017/10/14 06:00 [entrez] AID - 4237733 [pii] AID - 10.1093/infdis/jix497 [doi] PST - ppublish SO - J Infect Dis. 2017 Dec 12;216(11):1460-1470. doi: 10.1093/infdis/jix497.