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Genome-wide analysis of genetic risk factors for rheumatic heart disease in Australian Aboriginal populations from the Northern Territory
Names of investigators
Jenefer M. Blackwell, Timo Lassmann, Alexia Weeks, Denise Anderson, Genevieve Syn, Jonathan Carapetis
Rheumatic 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. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single nucleotide variants (SNVs) were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation were used to fine-map susceptibility to RHD to the human leukocyte antigen (HLA) region. This work was published in the Journal of Infectious Diseases in 2017. Deidentified genotype data for a subset of fully-consented individuals from this study are available for health-based studies through application to the Data Access Committee.
As a continuation of this project we are using whole exome sequencing (WES) (i.e. protein coding and adjacent regulatory sequences) to identify novel variants that may be associated with severe RHD and related clinical manifestations of GAS infection in this population. The data from this whole exome sequencing will also contribute to the reference panel of genetic variation in Australian Aboriginal populations that can be used to support other health-based research projects, as well as the diagnosis of rare diseases in Aboriginal children. WES was carried out using DNA from 50 individuals from the Northern Territory (NT) who had fully consented for continued use of their DNA and genetic data in future health-based research. The NT population had an average sequence depth of 89.8% at 20X coverage and 83.3% at 30X coverage. We also took the opportunity to re-analyse the WES data from the 72 Western Australian Aboriginal individuals studied previously using updated sequence analysis pipelines. The WA population had an average sequence depth of 82.2% at 20X coverage and 72.9% at 30X coverage. A total number of 289,829 variants were identified in at least one individual in the NT cohort and 248,374 variants were identified in at least one individual in the WA cohort. There were 166,719 variants present in both cohorts, whilst 123,110 variants were private to the NT cohort and 81,655 were private to the WA cohort. Of these, 8,801 and 12,363 non-synonymous SNVs (i.e. causing a change in the protein code) were identified in the WA and NT populations, respectively, that are not present in the public domain database for nonsynomous SNVs predicted to be functional (dbNSFP: PMID: 21520341). Of these 2,356 were present in both populations. This data set is being deposited in the European Genome Phenome Archive and will be available for health-based studies through application to the Data Access Committee. Data from these two studies provide useful reference data for health-based genomic studies on Aboriginal Australians.
Plain language summary
Genetic makeup can influence susceptibility to RHD caused by infection with Group A Streptococcus (GAS) which are particularly prevalent in Indigenous populations. Our research has identified one common genetic factor that determines susceptibility to disease in NT Aboriginal Australians. Continuing research aims to identify rarer genetic variants that contribute to susceptibility to this disease. The data obtained can also contribute to other health-based genetic studies in Aboriginal Australian populations, including in the diagnosis of rare genetic diseases.
Funders of the project
Heather A. D’Antoine, Melita McKinnon and Bo Reményi, Menzies School of Health Research, Darwin, NT, Australia
Dawn Bessarab, The University of Western Australia, WA, Australia
Ngiare Brown, The University of Wollongong, NSW, Australia
Steven Y.C. Tong, The University of Melbourne, Victoria, Australia
Andrew Steer, Royal Children’s Hospital, Melbourne, Victoria, Australia
Michael Inouye, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia, and University of Cambridge, UK
Head, Genetics & HealthEmail me
Feilman Fellow; Program Head, Genetics and Rare DiseasesEmail me
Executive Director; Head, Strep A and Rheumatic Heart Disease; Co-Founder of REACH08 6319 1000 Email me