The Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, OX3 7BN, UK.
Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, 226025, Uttar Pradesh, India.
Sci Rep. 2020 Jun 2;10(1):9004. doi: 10.1038/s41598-020-65855-8.
Rheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P = 3.48×10). Importantly, this signal remains despite conditioning on the lead class I and class II variants (P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.
风湿性心脏病（Rheumatic Heart Disease，RHD）是一种自身炎症性心脏病，最近被世界卫生组织列为全球卫生重点关注疾病。在此，我们报告了一项针对 1163 名南亚人（672 例病例；491 名对照）的风湿性心脏病易感性全基因组关联研究（GWAS），这些人是在印度和斐济招募的。我们分析了直接获得和推断的基因型，并在来自英国生物库研究的 1459 名欧洲人（150 例病例；1309 名对照）中对相关基因座进行了随访。我们在南亚人群数据集的人类白细胞抗原（HLA）复合物的 III 类区域中发现了一个新的易感性信号，该信号在欧洲人群中得到了明确的复制（rs201026476；合并优势比 1.81，95%置信区间 1.51-2.18，P = 3.48×10）。重要的是，即使在考虑到主要的 I 类和 II 类变体的情况下，这种信号仍然存在（P = 0.00033）。这些发现表明 III 类区域是风湿性心脏病易感性的关键决定因素，为发病机制提供了重要的新见解，同时部分解释了早期报告的不一致性。
