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bioRxiv · 10.1101/188334

Genome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicry

Gray, L.-A.·D'Antoine, H. A.·Tong, S. Y. C.·McKinnon, M.·Bessarab, D.·Brown, N.·Remenyi, B.·Steer, A.·Syn, G.·Blackwell, J. M.·Inouye, M.·Carapetis, J. R.
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Abstract

BackgroundRheumatic heart disease (RHD) following Group A Streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers pro-inflammatory cardiac valve-reactive T-cells.\n\nMethodsGenome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single nucleotide polymorphisms (SNPs) 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.\n\nResultsThe strongest genetic association was intronic to HLA-DQA1 (rs9272622; P=1.86x10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (OR 1.44, 95%CI 1.09-1.90, P=9.56x10-3) and HLA-DQA1*0103_DQB1*0601 (OR 1.27, 95%CI 1.07-1.52, P=7.15x10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P=2.36x10-3) 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 two risk haplotypes than the protective haplotype.\n\nConclusionsVariation 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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Gray, L.-A., D'Antoine, H. A., Tong, S. Y. C., McKinnon, M., Bessarab, D., Brown, N., Remenyi, B., Steer, A., Syn, G., Blackwell, J. M., Inouye, M., Carapetis, J. R.. 2017-09-13. Genome-wide analysis of genetic risk factors for rheumatic heart disease in Aboriginal Australians provides support for pathogenic molecular mimicry. https://doi.org/10.1101/188334

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