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Is susceptibility to rheumatic heart disease (RHD) heritable in African individuals, and if so, what are the common genetic variants associated with RHD risk?
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.
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.
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.
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.
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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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: March 25, 2021.
Published Online: June 9, 2021. doi:10.1001/jamacardio.2021.1627
Corresponding Author: Guillaume Paré, MD, MSc, Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton St E, Hamilton, ON L8L 2X2, Canada (firstname.lastname@example.org).
Author Contributions: Ms Machipisa and Dr Paré had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Engel and Paré contributed equally to this work.
Concept and design: Machipisa, Shaboodien, de Vries, Lwabi, Okello, Musuku, ElSayed, Elhassan, Zühlke, Mulder, Ramesar, Lesosky, Parks, Cordell, Engel, Paré.
Acquisition, analysis, or interpretation of data: Machipisa, Chong, Muhamed, Chishala, Pandie, Laing, Joachim, Daniels, Ntsekhe, Hugo-Hamman, Gitura, Ogendo, Okello, Damasceno, Novela, Mocumbi, Madeira, Musuku, Mtaja, ElSayed, Elhassan, Bode-Thomas, Okeahialam, Zühlke, Mulder, Lesosky, Parks, Cordell, Keavney, Engel, Paré.
Drafting of the manuscript: Machipisa, Chong, Shaboodien, Pandie, Ogendo, Okello, Madeira, Zühlke, Engel, Paré.
Critical revision of the manuscript for important intellectual content: Machipisa, Chong, Muhamed, Chishala, de Vries, Laing, Joachim, Daniels, Ntsekhe, Hugo-Hamman, Gitura, Lwabi, Okello, Damasceno, Novela, Mocumbi, Musuku, Mtaja, ElSayed, Elhassan, Bode-Thomas, Okeahialam, Zühlke, Mulder, Ramesar, Lesosky, Parks, Cordell, Keavney, Engel, Paré.
Statistical analysis: Machipisa, Chong, Pandie, Daniels, Lesosky, Parks, Paré.
Obtained funding: Machipisa, Hugo-Hamman, Okello, Zühlke, Cordell, Engel, Paré.
Administrative, technical, or material support: Machipisa, Muhamed, Chishala, Shaboodien, Laing, Daniels, Hugo-Hamman, Lwabi, Okello, Damasceno, Madeira, Musuku, ElSayed, Elhassan, Zühlke, Ramesar, Engel, Paré.
Supervision: Chong, Hugo-Hamman, Gitura, Lwabi, Damasceno, Musuku, ElSayed, Elhassan, Bode-Thomas, Zühlke, Mulder, Cordell, Keavney, Engel, Paré.
Conflict of Interest Disclosures: Ms Machipisa reported receiving grants from Wellcome Trust during the conduct of the study; nonfinancial support from H3Africa; attending a sponsored training course at Wellcome Genome Campus; was funded by the University of Cape Town (under the Mayosi Research Group RHDGen Fellowship funded by the Wellcome Trust) the Crasnow Travel Scholarship, and via Population Health Research Institute (PHRI) and McMaster University through the inaugural Bongani Mayosi UCT (University of Cape Town)-PHRI Scholarship 2019/2020 to complete the submitted work. Mr Chong reported receiving a Canadian Institute of Health Research doctoral award and consulting fees from Bayer. Ms Pandie reported receiving grants from Wellcome Trust during the conduct of the study. Dr Damasceno reported receiving grants from University of Cape Town during the conduct of the study. Dr Musuku reported receiving grants from Wellcome Trust during the conduct of the study. Dr Mtaja reported receiving nonfinancial support from Wellcome Trust during the conduct of the study. Dr Mulder reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Parks reported receiving grants from National Institute for Health Research during the conduct of the study and the British Medical Association. Dr Cordell reported receiving support from Newcastle University and the Wellcome Trust. Dr Keavney reported receiving support from the British Heart Foundation, the Wellcome Trust, and Manchester University. Dr Engel reported receiving support from the RHDGen Wellcome Trust grant, the South African National Research Foundation (NRF) No. 116287, grant NW17SFRN33630027 from the American Heart Association, and UCT. Dr Paré reported receiving grants from Bayer and Esperion; personal fees from Bayer, Bristol Myers Squibb, Lexicomp, Amgen, Illumina, and Sanofi; and the Canada Research Chair in Genetic and Molecular Epidemiology, and CISCO Professorship in Integrated Health Systems outside the submitted work. No other disclosures were reported.
Funding/Support: RHDGen (https://h3africa.org/index.php/consortium/the-rhdgen-network-genetics-of-rheumatic-heart-disease-and-molecular-epidemiology-of-streptococcus-pyogenes-pharyngitis) was supported by grants awarded from the Wellcome Trust under the H3Africa; grant099313/B/12/A (https://app.dimensions.ai/details/grant/grant.3640606 and https://europepmc.org/grantfinder/grantdetails?query=pi%3A%22Mayosi%2BBM%22%2Bgid%3A%22099313%22%2Bga%3A%22Wellcome%20Trust%22).
Role of the Funder/Sponsor: Wellcome Trust under the H3Africa arm, provided the grant and received project progress reports at H3Africa meetings and other internal reviews. These meetings provided the funder with all details and the opportunity to provide input to the principal investigator’s plans regarding the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We would like to thank all participants for being a part of this study, as well as the members of the Mayosi Research Group Coordinating Office team and collaborating sites’ staff for the study coordination, recruitment, data entry, and cleaning. We also thank the Genetics of Rheumatic Heart Disease (RHDGen) Network Consortium members listed in eAppendix 1 in the Supplement. We acknowledge the Hatter Institute of Cardiovascular Research in Africa (HICRA), directed by Karen Sliwa, MD PhD, and its cardiovascular genetics laboratory for assisting with all of the preliminary wet laboratory work (primarily, students and staff funded by the Mayosi Research Group or RHDGen, namely: Maryam Fish, PhD, Gaurang Deshpande, PhD, Stephen Kamuli, MSc, Timothy Spracklen, PhD, Lameez Pearce, BSc, Janine Saaiman, and Zukiswa Jiki, BSc). We would also like to thank staff like Reina Ditta, MSc, of the Genetic and Molecular Epidemiology Laboratory (GMEL) for managing the laboratory and notably, Amanda Hodge, Gianluca Situm, BSc, Gillian Lampkin, BSc and Taylor MacIsaac, BSc, for assisting with the GMEL wet laboratory work. Also, we acknowledge the GMEL dry laboratory and PHRI students, affiliates, and members for providing technical consultations (especially Jenny Sjaarda, PhD, Pedrum Mohammadi-Shemirani, MSc, Marie Pigeyre, MD, PhD, Ricky Lali, MSc, Shihong Mao, PhD, Loubna Akhbir, PhD, Amel Lamri, PhD, Ann Le, MSc, Godsent Isiguzo, MD, PhD, Tinashe Chikowore, PhD, Rob Morton, PhD, Viwe Mtwise, MD, MMed, and Alexander P. Benz, MD MSc). We thank the Pacific Islands Rheumatic Heart Disease Genetics Network, South Asia Rheumatic Heart Disease Genetics Network and the UK Biobank Resource (application 11537) on which pooled analyses were based. Finally, we would like to thank everyone who took the time to provide valuable input throughout this study.
Additional Information: This article is dedicated to the memory of our mentor, friend, and colleague Bongani M Mayosi, MD, DPhil (1967-2018), who inspired and established the RHDGen Network Consortium through his great vision, leadership, guidance, and mentorship. This article is also dedicated to the memory of Lungile Pepeta, MD, recruitment site cardiologist, and Veronica Francis, RN, study coordinator, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. Genotype and phenotype data used in this article will be deposited in the Pan African Bioinformatics Network for the Human Heredity and Health in Africa (H3ABioNet) Data Archive, as per the H3Africa guidelines.79 Some additional restrictions on access and use apply (eg, focus on RHD research). Access to certain components of the dataset requires regulatory approval from the country where the samples were obtained. The H3A BioNet Data Archive repository will provide further information about access to the dataset (link: will be provided by H3AbioNet & European Genome-phenome Archive). Please cite this article whenever any data or method provided in the resources mentioned above is used. A complete list of individuals who worked in The Genetics of Rheumatic Heart Disease (RHDGen) Network Consortium is provided in eAppendix 1 in the Supplement.
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