• To collect saliva DNA samples from 500 Indigenous RHD patients and 1000 matched controls – participants of a similar age – for genotyping to better understand the pathogenesis (development patterns) of Rheumatic Heart Disease (RHD), which could lead to better treatments and improve the genetic literacy of key stakeholders.
  • To carefully and ethically conduct large-scale genetic research in an Australian Aboriginal and Torres Strait Islander context;
  • Determine the genetic associations of susceptibility to RHD in Indigenous Australian communities.

Even though RHD is preventable, Australia has the highest recorded rates of the disease in the world. Many RHD sufferers in Australia die either because their disease is so severe that surgery can’t help, or because they don’t get a chance to even consider surgery.

Indigenous Australians are up to eight times more likely than non-Indigenous Australians to be hospitalised for Acute Rheumatic Fever (ARF) and RHD. They are 20 times more likely to die from the condition too.

On average, Indigenous people die from RHD in their mid-thirties, compared to non-Indigenous people with the same disease who can expect to live well into their sixties.

Many Indigenous people will get group A streptococcus infections but only some will develop RHD. It’s not well understood why some people are susceptible to RHD and others aren’t.

Enter RHD Genetics, a new collaborative study into the role genetics plays in the disease’s presence and progression.

Implications for policy and practice:

This was one of the largest genetics research projects to be conducted in the Australian Indigenous population.  The research outcomes from this project will facilitate future genetic research in Indigenous populations in Australia and lead to better methods of diagnosing, treating and preventing rheumatic fever (RF) and rheumatic heart disease (RHD).  

  1. With the development of culturally appropriate sample and data collection and storage guidelines, information tools and research frameworks we are confident that future genetic research can be conducted with Australian Aboriginal communities and populations that will serve to close the gap in health disparity. 
  2. Out of the whole genome (3 billion DNA letters), we have found one particular area that may be associated with RHD. We are now doing more detailed work to confirm this and determine whether there are some specific DNA letters in this region linked directly to having an increased risk of getting RHD. If we do confirm this, it may help us better understand why and how RHD occurs, and potentially lead to better ways of diagnosing, treating and preventing RHD.

With the average cost of treatment being $500,000 per RHD patient in Australia our research could significantly impact the expenditure in the health sector with better diagnostic, therapeutic and prevention strategies.  Most importantly though we could significantly impact the premature morbidity and mortality experienced by a high proportion of Australian Aboriginal people diagnosed with RHD.  


Rheumatic heart disease occurs following acute rheumatic fever caused by infection with bacteria known as Group A Streptococcus.  Not everyone who becomes infected with Group A Streptococcus and gets acute rheumatic fever goes on to get rheumatic heart disease.  Previous studies had suggested that rheumatic heart disease is due to inflammation, especially in the valves that pump blood in the heart, caused by an auto-immune response.  That is, the individual’s immune system begins to see molecules that make up heart tissue as foreign bodies and makes an inflammatory response to try to get rid of them.  The big questions were, how does the bacterial infection trick the immune system into recognising heart tissue as foreign, and why do only some people do this?  One clue was that rheumatic heart disease tends to run in families, and so this study set out to find genetic risk factors for rheumatic heart disease. 

Since the sequencing of the human genome, it has become possible to look at variations in DNA between individuals across their whole genome, and to determine whether any of these variants are associated with disease.  We call this a genome-wide association study.  To carry out the study, we needed DNA from both rheumatic heart disease cases and from individuals who had never had disease.  Altogether we collected DNA from 1263 Aboriginal Australians (398 rheumatic heart disease cases; 865 controls), and looked at 4.5 million genetic variants across the genomes of each of these individuals.  When we analysed the data we obtained very strong statistical support (a 1 in 18 million chance that we were wrong) for one major signal for association with rheumatic heart disease that mapped to a region of chromosome 6 called the human leukocyte antigen (HLA) complex.  This region of the genome contains a large cluster of genes that control the immune response to infection, as well as autoimmune responses.  To find the genes within this complex that were responsible for rheumatic heart disease in this population of Aboriginal Australians, we carried out more detailed analysis of DNA sequences across the region.  We pinpointed two genes, called HLA-DQA1 and HLA-DQB1, that together make up a molecule on the surface of immune cells called dendritic cells that recognise bits of proteins from invaders like bacteria, chomp them up, and present them to a second kind of immune cell, called T cells.  The T cells then circulate round the body and trigger inflammation to get rid of the infection.  The trick we discovered was that individuals who had rheumatic heart disease were more likely than unaffected individuals to have versions of these HLA molecules that allowed them to recognise and present bits of proteins from certain strains of Group A Streptococcus.  More importantly, that the bits of the bacterial proteins that they recognised were very similar or identical to some of the proteins normally found in the heart.  This has been termed molecular mimicry in the past, but our study now helps us to understand why only some people recognise these bacterial proteins that trigger T cells to make inflammation in the heart.  This study has made a major contribution to our understanding of how rheumatic heart disease develops, providing important leads to guide current and future vaccine development as well as opening avenues to identify immune therapies.  It may even be possible to use this information to target treatments and vaccines to people most likely to develop RHD.

Project manager:
Contact information:
Project dates:

July 2012 to December 2015


  • National Health and Medical Research Council (NHMRC)
  • Walter and Eliza Hall Institute (WEHI)
  • University of Melbourne
  • Curtin University
  • Telethon Institute of Child Health Research
  1. Gray LA, D'Antoine HA, Tong SYC, McKinnon M, Bessarab D, Brown N, Reményi B, Steer A, Syn G, Blackwell JM, Inouye M, Carapetis JR. Genome-Wide Analysis of Genetic Risk Factors for Rheumatic Heart Disease in Aboriginal Australians Provides Support for Pathogenic Molecular Mimicry. J Infect Dis. 2017 Dec 12;216(11):1460-1470. doi: 10.1093/infdis/jix497. PMID: 29029143.
  2. Tong SY, D'Antoine H, McKinnon M, Turner K, Hudson M, Brown N, Carapetis JR, Bessarab DC. Lessons learned in genetic research with Indigenous Australian participants. Med J Aust. 2020 Mar;212(5):200-202.e1. doi: 10.5694/mja2.50499. Epub 2020 Feb 4. PMID: 32017112.
  3. Weeks AL, D'Antoine HA, McKinnon M, Syn G, Bessarab D, Brown N, Tong SYC, Reményi B, Steer A, Gray LA, Inouye M, Carapetis JR, Blackwell JM, Lassmann T. Reference exome data for Australian Aboriginal populations to support health-based research. Sci Data. 2020 Apr 29;7(1):129. doi: 10.1038/s41597-020-0463-1. PMID: 32350262; PMCID: PMC7190730.