Tafadzwa Machipisa1,2,3,4,5, Michael Chong3,4,5, Babu Muhamed1,2,3,4,5, Chishala Chishala1,2, Gasnat Shaboodien1,2, Shahiemah Pandie1, Jantina de Vries1, Nakita Laing1, Alexia Joachim1, Rezeen Daniels1, Mpiko Ntsekhe1, Christopher T Hugo-Hamman6, Bernard Gitura7, Stephen Ogendo7, Peter Lwabi8, Emmy Okello8, Albertino Damasceno9, Celia Novela9, Ana O Mocumbi10, Goeffrey Madeira11, John Musuku12, Agnes Mtaja12, Ahmed ElSayed13, Huda H M Elhassan13, Fidelia Bode-Thomas14, Basil N Okeahialam14, Liesl J Zühlke1,15, Nicola Mulder16, Raj Ramesar17, Maia Lesosky1, Tom Parks18, Heather J Cordell19, Bernard Keavney20,21, Mark E Engel1, Guillaume Paré3,4,5,22. 1. Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. 2. Hatter Institute for Cardiovascular Diseases Research in Africa and Cape Heart Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. 3. Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada. 4. Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada. 5. Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada. 6. Rheumatic Heart Disease Clinic, Windhoek Central Hospital, Ministry of Health and Social Services, Windhoek, Republic of Namibia. 7. Cardiology Department of Medicine, Kenyatta National Hospital, University of Nairobi, Nairobi, Kenya. 8. Uganda Heart Institute, Kampala, Uganda. 9. Faculty of Medicine, Eduardo Mondlane University/Nucleo de Investigaçao, Departamento de Medicina, Hospital Central de Maputo, Maputo, Mozambique. 10. Instituto Nacional de Saúde Ministério da Saúde, Maputo, Moçambique. 11. Emergency Department, World Health Organization Mozambique, Maputo, Mozambique. 12. Department of Paediatrics and Child Health, University Teaching Hospital-Children's Hospital, University of Zambia, Lusaka, Zambia. 13. Department of Cardiothoracic Surgery, Alshaab Teaching Hospital, Alazhari Health Research Center, Alzaiem Alazhari University, Khartoum, Sudan. 14. Department of Paediatrics, Jos University Teaching Hospital and University of Jos, Jos, Plateau State Nigeria. 15. Division of Paediatric Cardiology, Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and University of Cape Town, South Africa. 16. Computational 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. 17. Department of Pathology, University of Cape Town, Cape Town, South Africa. 18. Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 19. Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom. 20. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, United Kingdom. 21. Manchester University National Health Service Foundation Trust, Manchester Academic Health Science CentreManchester, United Kingdom. 22. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton Ontario, Canada.
Abstract
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.
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.
Authors: Juliane Franco; Bruno R Nascimento; Andrea Z Beaton; Kaciane K B Oliveira; Marcia M Barbosa; Sanny Cristina C Faria; Nayana F Arantes; Luana A Mello; Maria Cecília L Nassif; Guilherme C Oliveira; Breno C Spolaor; Carolina F Campos; Victor R H Silva; Marcelo Augusto A Nogueira; Antonio L Ribeiro; Craig A Sable; Maria Carmo P Nunes Journal: Pathogens Date: 2022-01-24
Authors: M Taariq Salie; Jing Yang; Bernard Keavney; Mark E Engel; Carlos R Ramírez Medina; Liesl J Zühlke; Chishala Chishala; Mpiko Ntsekhe; Bernard Gitura; Stephen Ogendo; Emmy Okello; Peter Lwabi; John Musuku; Agnes Mtaja; Christopher Hugo-Hamman; Ahmed El-Sayed; Albertino Damasceno; Ana Mocumbi; Fidelia Bode-Thomas; Christopher Yilgwan; Ganiyu A Amusa; Esin Nkereuwem; Gasnat Shaboodien; Rachael Da Silva; Dave Chi Hoo Lee; Simon Frain; Nophar Geifman; Anthony D Whetton Journal: Clin Proteomics Date: 2022-03-22 Impact factor: 3.988
Authors: Joselyn Rwebembera; Bruno Ramos Nascimento; Neema W Minja; Sarah de Loizaga; Twalib Aliku; Luiza Pereira Afonso Dos Santos; Bruno Fernandes Galdino; Luiza Silame Corte; Vicente Rezende Silva; Andrew Young Chang; Walderez Ornelas Dutra; Maria Carmo Pereira Nunes; Andrea Zawacki Beaton Journal: Pathogens Date: 2022-01-28