Dataset Information

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

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.

SUBMITTER: Machipisa T

PROVIDER: S-EPMC8190704 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Machipisa Tafadzwa T Chong Michael M Muhamed Babu B Chishala Chishala C Shaboodien Gasnat G Pandie Shahiemah S de Vries Jantina J Laing Nakita N Joachim Alexia A Daniels Rezeen R Ntsekhe Mpiko M Hugo-Hamman Christopher T CT Gitura Bernard B Ogendo Stephen S Lwabi Peter P Okello Emmy E Damasceno Albertino A Novela Celia C Mocumbi Ana O AO Madeira Goeffrey G Musuku John J Mtaja Agnes A ElSayed Ahmed A Elhassan Huda H M HHM Bode-Thomas Fidelia F Okeahialam Basil N BN Zühlke Liesl J LJ Mulder Nicola N Ramesar Raj R Lesosky Maia M Parks Tom T Cordell Heather J HJ Keavney Bernard B Engel Mark E ME Paré Guillaume G

JAMA cardiology 20210901 9

<h4>Importance</h4>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.<h4>Objective</h4>To identify common genetic loci associated with RHD susceptibility in Black African individuals.<h4>Design, setting, an ...[more]

PMID: 34106200

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Project description:ImportanceA genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis.ObjectiveTo estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals.Design, setting, and participantsRetrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020.ExposuresTTR Val122Ile (rs76992529) genotype.Main outcome and measuresThe primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors.ResultsAmong 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes.Conclusions and relevanceAmong a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.

Project description:BackgroundRheumatic heart disease (RHD) prevalence and mortality rates remain especially high in many parts of Africa. While effective prevention and treatment exist, coverage rates of the various interventions are low. Little is known about the comparative cost-effectiveness of different RHD interventions in limited resource settings. We developed an economic evaluation tool to assist ministries of health in allocating resources and planning RHD control programs.Methodology/principal findingsWe constructed a Markov model of the natural history of acute rheumatic fever (ARF) and RHD, taking transition probabilities and intervention effectiveness data from previously published studies and expert opinion. Our model estimates the incremental cost-effectiveness of scaling up coverage of primary prevention (PP), secondary prevention (SP) and heart valve surgery (VS) interventions for RHD. We take a healthcare system perspective on costs and measure outcomes as disability-adjusted life-years (DALYs), discounting both at 3%. Univariate and probabilistic sensitivity analyses are also built into the modeling tool. We illustrate the use of this model in a hypothetical low-income African country, drawing on available disease burden and cost data. We found that, in our hypothetical country, PP would be cost saving and SP would be very cost-effective. International referral for VS (e.g., to a country like India that has existing surgical capacity) would be cost-effective, but building in-country VS services would not be cost-effective at typical low-income country thresholds.Conclusions/significanceOur cost-effectiveness analysis tool is designed to inform priorities for ARF/RHD control programs in Africa at the national or subnational level. In contrast to previous literature, our preliminary findings suggest PP could be the most efficient and cheapest approach in poor countries. We provide our model for public use in the form of a Supplementary File. Our research has immediate policy relevance and calls for renewed efforts to scale up RHD prevention.

Dataset Information

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

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Publications

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

Similar Datasets

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