Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry

Lesley Ann Gray, Heather A. D'Antoine, Steven Y.C. Tong, Melita McKinnon, Dawn Bessarab, Ngiare Brown, Bo Reményi, Andrew Steer, Genevieve Syn, Jenefer M. Blackwell, Michael Inouye, Jonathan R. Carapetis

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish
    Pages (from-to)1460-1470
    Number of pages11
    JournalThe Journal of infectious diseases
    Volume216
    Issue number11
    DOIs
    Publication statusPublished - 12 Dec 2017

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  • Cite this

    Gray, L. A., D'Antoine, H. A., Tong, S. Y. C., McKinnon, M., Bessarab, D., Brown, N., Reményi, B., Steer, A., Syn, G., Blackwell, J. M., Inouye, M., & Carapetis, J. R. (2017). Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry. The Journal of infectious diseases, 216(11), 1460-1470. https://doi.org/10.1093/infdis/jix497