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

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 (23%), and other ethnicities (11%). 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.

Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association

“…94,95 The RHDGen Network study (Genetics of Rheumatic Heart Disease) recently collected samples from 2548 patients with RHD and 2261 control subjects from 8 African countries. 147 This study replicated a previously reported genetic association with the immunoglobulin heavy chain locus (IGH) 148 and revealed several suggestive loci, including a novel susceptibility locus on chromosome 11 exclusive to Black African individuals. 149 Potential Therapeutic Targets Targeted therapy for RHD remains limited.…”

Echocardiographic Screening of Rheumatic Heart Disease: Current Concepts and Challenges

“…Evidence suggests that ARF is an autoimmune response to pharyngeal disease, and there may be a genetic predisposition component. 3 Streptococcal antigens activate the humoral and cell-dependent immune systems and cause tissue injury by cross-reacting with human proteins. 4 The structural similarity between myosin epitopes and heart valve proteins such as laminin and vimentin is thought to be responsible for antibody-dependent damage to the heart valves.…”