The Human Leukocyte Antigen Locus and Susceptibility to Rheumatic Heart Disease in South Asians and Europeans

Background Rheumatic heart disease (RHD) remains an important cause of morbidity and mortality globally. Several reports have linked the disease to the human leukocyte antigen (HLA) locus but with negligible consistency. Methods We undertook a genome-wide association study (GWAS) of susceptibility to RHD in 1163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1459 Europeans (150 cases; 1309 controls) from the UK Biobank study. For fine-mapping, we used HLA imputation to define classical alleles and amino acid polymorphisms. Results A single signal situated in the HLA class III region reached genome-wide significance in the South Asians, and replicated in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P =3.48×10−10). While the signal fine-mapped to specific amino acid polymorphisms within HLA-DQB1 and HLA-B , with conditioning, the lead class III variant remained associated with susceptibility ( P =3.34×10−4), suggesting an independent effect. Conclusions A complex HLA signal, likely comprising at least two underlying causal variants, strongly associates with susceptibility to RHD in South Asians and Europeans. Crucially, the involvement of the class III region may partly explain the previous inconsistency, while offering important new insight into pathogenesis. ### Competing Interest Statement Dr. Cairns reports grants from British Heart Foundation during the conduct of the study; Dr. Mentzer reports grants from Wellcome Trust, grants from National Institute for Health Research during the conduct of the study; Dr. Hill reports grants from Wellcome Trust, grants from European Research Council during the conduct of the study; and Dr. Parks reports grants from British Heart Foundation, grants from National Institute for Health Research, grants from British Medical Association, grants from Medical Research Council during the conduct of the study. ### Funding Statement This research was supported by grants awarded to T.P. from the National Institute for Health Research (ACF-2016-20-001), British Heart Foundation (PG/14/26/30509), the Medical Research Council (G1100449) and the British Medical Association (Josephine Lansdell Grant 2018; Josephine Lansdell Grant 2012), and to B.J.C. from the British Heart Foundation Centre of Research Excellence, Oxford (RE/13/1/30181). A.J.M. was supported by a Wellcome Trust Fellowship with reference 106289/Z/14/Z and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). A.V.S.H. is supported by a Wellcome Trust Senior Investigator Award (HCUZZ0) and by a European Research Council advanced grant (294557). None of these funders had any role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the High-Throughput Genomics Group at the Wellcome Centre for Human Genetics for generating the genotyping and sequencing data, subsidized by a core award from the Wellcome Trust (090532/Z/09/Z). Computation used the Oxford Biomedical Research Computing (BMRC) facility, a joint development between the Wellcome Centre for Human Genetics and the Big Data Institute supported by Health Data Research UK and the NIHR Oxford Biomedical Research Centre. Financial support was provided by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Yes Genotype and phenotype data underlying the manuscript have been deposited in the European Genome-phenome Archive under accession numbers EGAS00001001881 and EGAS00001003565.