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Original Investigation
June 9, 2021

Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study

Author Affiliations
  • 1Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
  • 2Hatter Institute for Cardiovascular Diseases Research in Africa and Cape Heart Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa
  • 3Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
  • 4Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada
  • 5Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada
  • 6Rheumatic Heart Disease Clinic, Windhoek Central Hospital, Ministry of Health and Social Services, Windhoek, Republic of Namibia
  • 7Cardiology Department of Medicine, Kenyatta National Hospital, University of Nairobi, Nairobi, Kenya
  • 8Uganda Heart Institute, Kampala, Uganda
  • 9Faculty of Medicine, Eduardo Mondlane University/Nucleo de Investigaçao, Departamento de Medicina, Hospital Central de Maputo, Maputo, Mozambique
  • 10Instituto Nacional de Saúde Ministério da Saúde, Maputo, Moçambique
  • 11Emergency Department, World Health Organization Mozambique, Maputo, Mozambique
  • 12Department of Paediatrics and Child Health, University Teaching Hospital–Children’s Hospital, University of Zambia, Lusaka, Zambia
  • 13Department of Cardiothoracic Surgery, Alshaab Teaching Hospital, Alazhari Health Research Center, Alzaiem Alazhari University, Khartoum, Sudan
  • 14Department of Paediatrics, Jos University Teaching Hospital and University of Jos, Jos, Plateau State Nigeria
  • 15Division of Paediatric Cardiology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and University of Cape Town, South Africa
  • 16Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
  • 17Department of Pathology, University of Cape Town, Cape Town, South Africa
  • 18Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
  • 19Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom
  • 20Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom
  • 21Manchester University National Health Service Foundation Trust, Manchester Academic Health Science CentreManchester, United Kingdom
  • 22Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton Ontario, Canada
JAMA Cardiol. 2021;6(9):1000-1011. doi:10.1001/jamacardio.2021.1627
Key Points

Question  Is susceptibility to rheumatic heart disease (RHD) heritable in African individuals, and if so, what are the common genetic variants associated with RHD risk?

Findings  In this genome-wide association study of 4809 African individuals, 1 genetic risk locus at 11q24.1 (rs1219406) was associated with RHD at genome-wide significance in Black African individuals but not in other groups, although 1 previously described association was replicated at nominal significance. Polygenic heritability of RHD is estimated at 0.49 in African individuals.

Meaning  This study suggests that there is an important polygenic component to RHD risk in African individuals, highlighting genetic features exclusive to African individuals as well as genetic similarities with non-African individuals.


Importance  Rheumatic heart disease (RHD), a sequela of rheumatic fever characterized by permanent heart valve damage, is the leading cause of cardiac surgery in Africa. However, its pathophysiologic characteristics and genetics are poorly understood. Understanding genetic susceptibility may aid in prevention, control, and interventions to eliminate RHD.

Objective  To identify common genetic loci associated with RHD susceptibility in Black African individuals.

Design, Setting, and Participants  This multicenter case-control genome-wide association study (GWAS), the Genetics of Rheumatic Heart Disease, examined more than 7 million genotyped and imputed single-nucleotide variations. The 4809 GWAS participants and 116 independent trio families were enrolled from 8 African countries between December 31, 2012, and March 31, 2018. All GWAS participants and trio probands were screened by use of echocardiography. Data analyses took place from May 15, 2017, until March 14, 2021.

Main Outcomes and Measures  Genetic associations with RHD.

Results  This study included 4809 African participants (2548 RHD cases and 2261 controls; 3301 women [69%]; mean [SD] age, 36.5 [16.3] years). The GWAS identified a single RHD risk locus, 11q24.1 (rs1219406 [odds ratio, 1.65; 95% CI, 1.48-1.82; P = 4.36 × 10−8]), which reached genome-wide significance in Black African individuals. Our meta-analysis of Black (n = 3179) and admixed (n = 1055) African individuals revealed several suggestive loci. The study also replicated a previously reported association in Pacific Islander individuals (rs11846409) at the immunoglobulin heavy chain locus, in the meta-analysis of Black and admixed African individuals (odds ratio, 1.16; 95% CI, 1.06-1.27; P = 1.19 × 10−3). The HLA (rs9272622) associations reported in Aboriginal Australian individuals could not be replicated. In support of the known polygenic architecture for RHD, overtransmission of a polygenic risk score from unaffected parents to affected probands was observed (polygenic transmission disequilibrium testing mean [SE], 0.27 [0.16] SDs; P = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12; P = 3.28 × 10−5) in Black African individuals.

Conclusions and Relevance  This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.

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