Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals: Findings From the RHDGen Study.
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Machipisa Tafadzwa, Chong Michael, Muhamed Babu, Chishala Chishala, Shaboodien Gasnat, Pandie Shahiemah, de Vries Jantina, Laing Nakita, Joachim Alexia, Daniels Rezeen, Ntsekhe Mpiko, Hugo-Hamman Christopher T, Gitura Bernard, Ogendo Stephen, Lwabi Peter, Okello Emmy, Damasceno Albertino, Novela Celia, Mocumbi Ana O, Madeira Goeffrey, Musuku John, Mtaja Agnes, ElSayed Ahmed, Elhassan Huda H M, Bode-Thomas Fidelia, Okeahialam Basil N, Zühlke Liesl J, Mulder Nicola, Ramesar Raj, Lesosky Maia, Parks Tom, Cordell Heather J, Keavney Bernard, Engel Mark E, Paré Guillaume
Аннотация
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.