Clinical Testing, DNA sample being prepared for testing in the lab.Credit: Cavan Images/ Getty Images
The 29-year-old South African woman had already lost her mother and older brother to heart disease when her enrolment in the University of Cape Town’s (UCT) cardiovascular health study saved her life.
Her younger brother may also have died if the investigations had not revealed a familial mutation in a known cardiac gene. This enabled tailored medical therapy for affected family members, and predictive genetic testing and clinical follow-up for their children and other relatives.
This family, along with more than 60 other families and over 800 unrelated individuals with cardiomyopathy in South Africa and Mozambique, are part of the seminal African Cardiomyopathy and Myocarditis Registry Programme (IMHOTEP), designed to interrogate the disproportionately high heart failure rates due to cardiomyopathies among young people in Africa.
The results are a significant step towards addressing the historic underrepresentation of people of African descent in genetic studies, opening the way to rectify inequitable access to the benefits of medical genomics.
“Currently, about 80% of participants in genome-wide association studies (GWAS) are of European descent,” says Gasnat Shaboodien, Director of Cardiovascular Genetics at the Cape Heart Institute at UCT, and a key contributor to the study.
Compounding the challenge, she points out, is that the 3% of data from people of African descent, previously being used for genetic studies, fell even lower in 2021, to just 1.1%. This may be due to less data from Africa being available when compared to Europe. In effect, this means African populations increasingly fail to benefit from genomic research, including early detection of disease.
Africa’s largely untapped broad genetic diversity provides fertile ground for pioneering studies like IMHOTEP, says UCT’s Ntobeko Ntusi, who leads the project, in collaboration with Oxford University’s Professor of Medicine, Hugh Watkins.
The international significance of the findings, Ntusi explains, lies in the fact that the study has identified a “completely different picture” of heart muscle disease amongst Africans, when compared to North America, the United Kingdom and Europe. Patients are younger, more women than men are affected, and most previously listed mutant gene variants aren’t a match.
“We found that one in every three of those recruited for the study have clear familial disease, or genetic cardiomyopathy, while another third have a secondary cardiomyopathy. The remainder are idiopathic (no known cause), perhaps also due to presently undiscovered genetic mutations,” Ntusi says, explaining that the genetic work became a big focus of the programme.
Against the background of a “lopsided” understanding of genetic medicine due to the dearth of African centred studies, Shaboodien points to the major scientific opportunities that have been missed – and the serious negative impacts for the development of effective health policies on the continent.
“Adequate information on cardiomyopathies in African populations is so lacking that it has simply been impossible to make informed decisions for the continent,” she says.
According to the World Health Organization, more than three-quarters of all deaths from noncommunicable deaths occur in low- and middle-income countries. Cardiovascular diseases account for most of those, highlighting the urgency of curbing preventable illness and death that is putting young people in Africa at such high risk.
The IMHOTEP study, which has so far supported 13 postgraduate students, was established by UCT investigators in 2014. The initial aim was to recruit 750 participants from South Africa and Mozambique, but that grew to more than 1,000, with a continent-wide cohort of 10,000 to 15,000 planned for the next phase next year.
Among the key early findings, some of which have already been reported, is that African patients with heart muscle disease are much younger than in other parts of the world and they are more likely to include young women who suffer from peripartum cardiomyopathy. This condition is diagnosed during pregnancy or after giving birth.
The researchers also found a predominance of dilated cardiomyopathy among the African patients, which occurs when the chamber size or ventricle is big and the wall thinned, affecting the way in which the heart contracts. This is often associated with heart failure and premature death.
This was true for 72% of the adults and an even higher percentage of the children, who accounted for 25% of the study recruits.
“If you look at research reports coming out of North America, the United Kingdom and Europe, they find that hypertrophic forms of cardiomyopathy (when the ventricle walls are thickened, and contract vigorously) are by far the commonest,” Ntusi says.
Hypertrophic cardiomyopathy also runs in families. But when the UCT team took a targeted sequencing chip from the UK, which had been validated there, in North America and in Europe, they found that instead of the expected 60% to 70% yield for identifying the underlying genetic mutations, it was much less effective for African populations.
Targeted or whole exome sequencing are types of genetic sequencing increasingly used to understand what mutations may be causing disease.
“When we applied it to black Africans, and excluded the common founder mutations that had previously been described among Africans of mixed ancestry or Afrikaner lineage, the yield was only 29%. So now we know that the genetic causes of heart muscle disease among Africans must be different,” he says.
Sarah Kraus, the study’s senior clinical researcher, currently based at Oxford University, is finalising the clinical data and genetic analysis for publication. She says the establishment of this first DNA repository for cardiomyopathies in Africa has already delivered results for many patients enrolled in IMHOTEP, by conducting targeted next generation sequencing for about 40 genes known to cause cardiomyopathy.
Scrutiny of identified mutations will determine whether they are in fact disease-causing, or are variants of unknown significance.
Critically, Kraus stresses, IMHOTEP’s patient-oriented research approach has boosted the availability of clinical care to patients.
Watkins concurs: “Over the last 25 years we have made substantial inroads into understanding the basis of cardiomyopathy, and using this to improve patient care. But this hasn’t really improved heaIth care in low- and middle-income nations.”
The IMHOTEP study, however, combines efforts to increase capacity and know-how, while also addressing “the big holes in our knowledge that otherwise precluded adoption of the standard of care (that is the norm) in Europe and the US”, he adds.
For Ntusi and the South African team, it marks a critical opportunity for “individuals at the coalface to lead the scholarship in a way that will directly benefit the populations they serve”.
With the availability of high-quality genomes from Africa, studies like IMHOTEP promise to add new chapters to the story of the continent’s origins, and change the trajectory of its ailing health systems.
