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.

重要性风湿性心脏病 (RHD) 是风湿热的后遗症，其特征是永久性心脏瓣膜损伤，是非洲心脏手术的主要原因。然而，对其病理生理学特征和遗传学知之甚少。了解遗传易感性可能有助于预防、控制和干预以消除 RHD。

目的确定与非洲黑人个体 RHD 易感性相关的常见遗传位点。

设计、设置和参与者这项多中心病例对照全基因组关联研究 (GWAS)，即风湿性心脏病遗传学，检查了超过 700 万个基因分型和估算的单核苷酸变异。 2012年12月31日至2018年3月31日期间，从8个非洲国家招募了4809名GWAS参与者和116个独立三人家庭。所有GWAS参与者和三人先证者均通过超声心动图进行筛查。数据分析时间为2017年5月15日至2021年3月14日。

主要结果和措施与 RHD 的遗传关联。

结果这项研究包括 4809 名非洲参与者（2548 名 RHD 病例和 2261 名对照者；3301 名女性 [69%]；平均 [SD] 年龄，36.5 [16.3] 岁）。 GWAS 确定了一个 RHD 风险位点 11q24.1（rs1219406 [比值比，1.65；95% CI，1.48-1.82；P = 4.36 × 10−8]），该位点在非洲黑人个体中达到全基因组显着性。我们对黑人 (n = 3179) 和混血 (n = 1055) 非洲人的荟萃分析揭示了几个暗示性基因座。该研究还在黑人和混血非洲个体的荟萃分析中复制了先前报道的太平洋岛民个体 (rs11846409) 免疫球蛋白重链位点的关联（优势比，1.16；95% CI，1.06-1.27；P = 1.19） × 10−3)。澳大利亚原住民个体中报告的 HLA (rs9272622) 关联无法复制。为了支持 RHD 的已知多基因架构，观察到多基因风险评分从未受影响的父母到受影响的先证者的过度传递（多基因传递不平衡测试平均值 [SE]，0.27 [0.16] SD；P = .04996），并且芯片-非洲黑人个体的遗传力估计高达 0.49（SE = 0.12；P = 3.28 × 10−5）。

结论和相关性这项研究揭示了非洲黑人个体特有的一个新的候选易感性位点，以及非洲个体 RHD 易感性的重要遗传成分。