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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\u20132.18,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20093.48\u00d710\n                    <jats:sup>\u221210<\/jats:sup>\n                    ). Importantly, this signal remains despite conditioning on the lead class I and class II variants (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.00033). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-020-65855-8","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T06:06:02Z","timestamp":1591077962000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The Human Leukocyte Antigen Locus and Rheumatic Heart Disease Susceptibility in South Asians and Europeans"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7583-2886","authenticated-orcid":false,"given":"Kathryn","family":"Auckland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balraj","family":"Mittal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Cairns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveen","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4502-2209","authenticated-orcid":false,"given":"Alexander J.","family":"Mentzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3121-4397","authenticated-orcid":false,"given":"Joseph","family":"Kado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3511-3297","authenticated-orcid":false,"given":"Mai Ling","family":"Perman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Steer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0900-9629","authenticated-orcid":false,"given":"Adrian V. 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