Association of Novel Locus With Rheumatic Heart Disease in Black African Individuals
Authors: Tafadzwa Machipisa, Michael Chong, Babu Muhamed, Chishala Chishala, Gasnat Shaboodien, Shahiemah Pandie, Jantina de Vries, Nakita Laing, Alexia Joachim, Rezeen Daniels, Mpiko Ntsekhe, Christopher T. Hugo-Hamman, Bernard Gitura, Stephen Ogendo, Peter Lwabi, Emmy Okello, Albertino Damasceno, Celia Novela, Ana O. Mocumbi, Goeffrey Madeira, John Musuku, Agnes Mtaja, Ahmed ElSayed, Huda H. M. Elhassan, Fidelia Bode-Thomas, Basil N. Okeahialam, Liesl J. Zühlke, Nicola Mulder, Raj Ramesar, Maia Lesosky, Tom Parks, Heather J. Cordell, Bernard Keavney, Mark E. Engel, Guillaume Paré
Journal: JAMA Cardiology (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> To identify common genetic loci associated with RHD susceptibility in Black African individuals. <h3>Design, Setting, and Participants</h3> 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. <h3>Main Outcomes and Measures</h3> Genetic associations with RHD. <h3>Results</h3> 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;<i>P</i> = 4.36 × 10<sup>−8</sup>]), 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;<i>P</i> = 1.19 × 10<sup>−3</sup>). The<i>HLA</i>(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;<i>P</i> = .04996), and the chip-based heritability was estimated to be high at 0.49 (SE = 0.12;<i>P</i> = 3.28 × 10<sup>−5</sup>) in Black African individuals. <h3>Conclusions and Relevance</h3> This study revealed a novel candidate susceptibility locus exclusive to Black African individuals and an important heritable component to RHD susceptibility in African individuals.