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

Abstract

Background. Rheumatic heart disease (RHD) afer group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proin?ammatory cardiac valve-reactive T cells. Methods. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Singlenucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fne-map the human leukocyte antigen (HLA) region. Epitope binding afnities were mapped for human cross-reactive GAS proteins, including M5 and M6. Results. Te strongest genetic association was intronic to HLA-DQA..