Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†

Tafadzwa Machipisa^{1

2

3

4

5}, Chishala Chishala^{1

6}, Gasnat Shaboodien^{1

2}, Liesl J Zühlke^{1

2

7

8}, Babu Muhamed^{1

2

3

4

5}, Shahiemah Pandie¹, Jantina de Vries¹, Nakita Laing¹, Alexia Joachim¹, Rezeen Daniels¹, Mpiko Ntsekhe¹, Christopher T Hugo-Hamman⁹, Bernard Gitura¹⁰, Stephen Ogendo¹¹, Peter Lwabi¹², Emmy Okello¹², Albertino Damasceno¹³, Celia Novela¹³, Ana O Mocumbi¹⁴, Geoffrey Madeira¹⁵, John Musuku¹⁶, Agnes Mtaja¹⁶, Ahmed ElSayed¹⁷, Huda H M Alhassan¹⁷, Fidelia Bode-Thomas¹⁸, Christopher Yilgwan¹⁸, Ganiyu Amusa¹⁸, Esin Nkereuwem¹⁸, Nicola Mulder¹⁹, Raj Ramesar²⁰, Maia Lesosky²¹, Heather J Cordell²², Michael Chong^{3

4

5}, Bernard Keavney^{23

24}, Guillaume Paré^#^{3

4

5

25}, Mark E Engel^#^{1

2}; RHDGen Network Consortium†

Affiliations

¹ Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa (T.M., C.C., G.S., L.J.Z., B.M., S.P.; J.d.V., N.L., A.J., R.D., M.N., M.E.E.).
² Department of Medicine, Cape Heart Institute, University of Cape Town, Cape Town, South Africa (T.M., G.S., L.J.Z., B.M., M.E.E.).
³ Population Health Research Institute, Hamilton, ON, Canada (T.M., B.M., M.C., G.P.).
⁴ Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada (T.M., B.M., M.C., G.P.).
⁵ Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada (T.M., B.M., M.C., G.P.).
⁶ Division of Cardiology, University of KwaZulu-Natal, Msunduzi, KwaZulu-Natal (C.C.).
⁷ Division of Pediatric Cardiology, Department of Pediatrics and Child Health, Red Cross War Memorial Children's Hospital, Cape Town, South Africa (L.J.Z.).
⁸ South African Medical Research Council, Extramural Research and Internal Portfolio, Cape Town, South Africa (L.J.Z.).
⁹ Rheumatic Heart Disease Clinic, Windhoek Central Hospital, Ministry of Health and Social Services, Windhoek, Republic of Namibia (C.T.H.-H.).
¹⁰ Cardiology Department of Medicine, Kenyatta National Hospital, University of Nairobi, Nairobi, Kenya (B.G.).
¹¹ Uganda Heart Inst, Departments of Adult and Pediatric Cardiology, Kampala, Uganda (S.O.).
¹² School of Medicine, Maseno Univ, Kenya (P.L., E.O.).
¹³ Faculty of Medicine, Eduardo Mondlane Univ/Nucleo de Investigaçao, Departamento de Medicina, Hospital Central de Maputo, Maputo, Mozambique (A.D., C.N.).
¹⁴ Instituto Nacional de Saúde Ministério da Saúde, Mozambique (A.O.M.).
¹⁵ WHO Mozambique, Maputo, Mozambique (G.M.).
¹⁶ University Teaching Hospital, Children's Hospital, University of Zambia, Lusaka, Zambia (J.M., A.M.).
¹⁷ Department of Cardiothoracic Surgery, Alshaab Teaching Hospital, Alazhari Health Research Centre, Alzaiem Alazhari University, Khartoum, Sudan (A.E., H.H.M.A.).
¹⁸ Deptartments of Pediatrics and Medicine, Jos University Teaching Hospital and University of Jos, Jos, Plateau State, Nigeria (F.B.-T., C.Y., G.A., E.N.).
¹⁹ Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences (N.M.), University of Cape Town, Cape Town, South Africa.
²⁰ Department of Pathology (R.R.), University of Cape Town, Cape Town, South Africa.
²¹ Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine (M.L.), University of Cape Town, Cape Town, South Africa.
²² Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK (H.J.C.).
²³ Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK (B.K.).
²⁴ Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, UK (B.K.).
²⁵ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada (G.P.).

^# Contributed equally.

PMID: 36548480
PMCID: PMC9946164
DOI: 10.1161/CIRCGEN.121.003641

Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†

Tafadzwa Machipisa et al. Circ Genom Precis Med. 2023 Feb.

. 2023 Feb;16(1):e003641.

doi: 10.1161/CIRCGEN.121.003641. Epub 2022 Dec 22.

Authors

Affiliations

¹ Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa (T.M., C.C., G.S., L.J.Z., B.M., S.P.; J.d.V., N.L., A.J., R.D., M.N., M.E.E.).
² Department of Medicine, Cape Heart Institute, University of Cape Town, Cape Town, South Africa (T.M., G.S., L.J.Z., B.M., M.E.E.).
³ Population Health Research Institute, Hamilton, ON, Canada (T.M., B.M., M.C., G.P.).
⁴ Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada (T.M., B.M., M.C., G.P.).
⁵ Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada (T.M., B.M., M.C., G.P.).
⁶ Division of Cardiology, University of KwaZulu-Natal, Msunduzi, KwaZulu-Natal (C.C.).
⁷ Division of Pediatric Cardiology, Department of Pediatrics and Child Health, Red Cross War Memorial Children's Hospital, Cape Town, South Africa (L.J.Z.).
⁸ South African Medical Research Council, Extramural Research and Internal Portfolio, Cape Town, South Africa (L.J.Z.).
⁹ Rheumatic Heart Disease Clinic, Windhoek Central Hospital, Ministry of Health and Social Services, Windhoek, Republic of Namibia (C.T.H.-H.).
¹⁰ Cardiology Department of Medicine, Kenyatta National Hospital, University of Nairobi, Nairobi, Kenya (B.G.).
¹¹ Uganda Heart Inst, Departments of Adult and Pediatric Cardiology, Kampala, Uganda (S.O.).
¹² School of Medicine, Maseno Univ, Kenya (P.L., E.O.).
¹³ Faculty of Medicine, Eduardo Mondlane Univ/Nucleo de Investigaçao, Departamento de Medicina, Hospital Central de Maputo, Maputo, Mozambique (A.D., C.N.).
¹⁴ Instituto Nacional de Saúde Ministério da Saúde, Mozambique (A.O.M.).
¹⁵ WHO Mozambique, Maputo, Mozambique (G.M.).
¹⁶ University Teaching Hospital, Children's Hospital, University of Zambia, Lusaka, Zambia (J.M., A.M.).
¹⁷ Department of Cardiothoracic Surgery, Alshaab Teaching Hospital, Alazhari Health Research Centre, Alzaiem Alazhari University, Khartoum, Sudan (A.E., H.H.M.A.).
¹⁸ Deptartments of Pediatrics and Medicine, Jos University Teaching Hospital and University of Jos, Jos, Plateau State, Nigeria (F.B.-T., C.Y., G.A., E.N.).
¹⁹ Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences (N.M.), University of Cape Town, Cape Town, South Africa.
²⁰ Department of Pathology (R.R.), University of Cape Town, Cape Town, South Africa.
²¹ Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine (M.L.), University of Cape Town, Cape Town, South Africa.
²² Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, International Centre for Life, Newcastle upon Tyne, UK (H.J.C.).
²³ Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK (B.K.).
²⁴ Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, UK (B.K.).
²⁵ Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada (G.P.).

^# Contributed equally.

PMID: 36548480
PMCID: PMC9946164
DOI: 10.1161/CIRCGEN.121.003641

Abstract

Background: The genetics of rheumatic heart disease (RHDGen) Network was developed to assist the discovery and validation of genetic variations and biomarkers of risk for rheumatic heart disease (RHD) in continental Africans, as a part of the global fight to control and eradicate rheumatic fever/RHD. Thus, we describe the rationale and design of the RHDGen study, comprising participants from 8 African countries.

Methods: RHDGen screened potential participants using echocardiography, thereafter enrolling RHD cases and ethnically-matched controls for whom case characteristics were documented. Biological samples were collected for conducting genetic analyses, including a discovery case-control genome-wide association study (GWAS) and a replication trio family study. Additional biological samples were also collected, and processed, for the measurement of biomarker analytes and the biomarker analyses are underway.

Results: Participants were enrolled into RHDGen between December 2012 and March 2018. For GWAS, 2548 RHD cases and 2261 controls (3301 women [69%]; mean age [SD], 37 [16.3] years) were available. RHD cases were predominantly Black (66%), Admixed (24%), and other ethnicities (10%). Among RHD cases, 34% were asymptomatic, 26% had prior valve surgery, and 23% had atrial fibrillation. The trio family replication arm included 116 RHD trio probands and 232 parents.

Conclusions: RHDGen presents a rare opportunity to identify relevant patterns of genetic factors and biomarkers in Africans that may be associated with differential RHD risk. Furthermore, the RHDGen Network provides a platform for further work on fully elucidating the causes and mechanisms associated with RHD susceptibility and development.

Keywords: cardiovascular diseases; genetics; infections; rheumatic heart disease.

PubMed Disclaimer

Figures

**Figure 1.**
Location of the Rheumatic Heart Disease Genetics (RHDGen) recruitment site countries (yellow) and regional sites (dark blue).

**Figure 2.**
**An example of the principal component analysis (PCA) from GCTA for the participants of the RHDGen GWAS and the trio family study.** NB: 1000G reference populations were from AFR (Black and African American), AMR (Ad Mixed American), EAS (East Asian), EUR (European) and SAS (South Asian) ancestries. From the 8 Sub-Saharan African countries in RHDGen, all populations self-reported as citizens/permanent residents of an African country. Hence, the “BLACK” group represents Black Africans, “ADMIXED” represents the “South African Coloureds” (SAC; ie, the same as the “Admixed Africans” description), “SUDANESE ARAB” are those who reside in Sudan and self-report being of Arab descent/ethnicity, “EUROPEAN” are those of European ancestry, “SOUTH ASIAN” are those of South Asian ancestry, “EAST ASIAN” are those of East Asian ancestry, and “NA” are those who did not self-report as identifying with any ethnicity/known ancestry.

See this image and copyright information in PMC

References

1. Beaton A, Kamalembo FB, Dale J, Kado JH, Karthikeyan G, Kazi DS, Longenecker CT, Mwangi J, Okello E, Ribeiro ALP. The American Heart Association’s call to action for reducing the global burden of rheumatic heart disease: a policy statement from the American Heart Association. Circulation. 2020;142:e358. doi: 10.1161/CIR.0000000000000922 - PubMed
1. Tissot C, da Cruz EM, Kalangos A, Buckvold S, Myers PO. Mitral Valve Anomalies and Related Disorders Critical Care of Children with Heart Disease. Springer; 2020.
1. Yuyun MF, Sliwa K, Kengne AP, Mocumbi AO, Bukhman G. Cardiovascular diseases in Sub-Saharan Africa compared to high-income countries: an epidemiological perspective. Glob Heart. 2020;15:15. doi: 10.5334/gh.403 - PMC - PubMed
1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, et al. ; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 STUDY. J Am Coll Cardiol. 2020;76:2982–3021. doi: 10.1016/j.jacc.2020.11.010 - PMC - PubMed
1. World Health Organization. Rheumatic fever and rheumatic heart disease, 2018: Executive Board, 141st Session: Resolutions and decisions, annexes, summary records. Geneva, Switzerland. Available at: https://www.who.int/cardiovascular_diseases/publications/trs923/en/

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†

Affiliations

Rationale, Design, and the Baseline Characteristics of the RHDGen (The Genetics of Rheumatic Heart Disease) Network Study†

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical