{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:27:29Z","timestamp":1790810849453,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T00:00:00Z","timestamp":1659571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54HG006938"],"award-info":[{"award-number":["U54HG006938"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001336","name":"University of the Witwatersrand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001336","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The complex pathogenesis of rheumatoid arthritis (RA) is not fully understood, with few studies exploring the genomic contribution to RA in patients from Africa. We report a genome-wide association study (GWAS) of South-Eastern Bantu-Speaking South Africans (SEBSSAs) with seropositive RA (n\u2009=\u2009531) and population controls (n\u2009=\u20092653). Association testing was performed using PLINK (logistic regression assuming an additive model) with sex, age, smoking and the first three principal components as covariates. The strong association with the Human Leukocyte Antigen (HLA) region, indexed by rs602457 (near HLA-DRB1), was replicated. An additional independent signal in the HLA region represented by the lead SNP rs2523593 (near the HLA-B gene; Conditional P-value\u2009=\u20096.4 \u00d7 10\u221210) was detected. Although none of the non-HLA signals reached genome-wide significance (P\u2009&amp;lt;\u20095 \u00d7 10\u22128), 17 genomic regions showed suggestive association (P\u2009&amp;lt;\u20095 \u00d7 10\u22126). The GWAS replicated two known non-HLA associations with MMEL1 (rs2843401) and ANKRD55 (rs7731626) at a threshold of P\u2009&amp;lt;\u20095 \u00d7 10\u22123 providing, for the first time, evidence for replication of non-HLA signals for RA in sub-Saharan African populations. Meta-analysis with summary statistics from an African-American cohort (CLEAR study) replicated three additional non-HLA signals (rs11571302, rs2558210 and rs2422345 around KRT18P39-NPM1P33, CTLA4-ICOS and AL645568.1, respectively). Analysis based on genomic regions (200 kb windows) further replicated previously reported non-HLA signals around PADI4, CD28 and LIMK1. Although allele frequencies were overall strongly correlated between the SEBSSA and the CLEAR cohort, we observed some differences in effect size estimates for associated loci. The study highlights the need for conducting larger association studies across diverse African populations to inform precision medicine-based approaches for RA in Africa.<\/jats:p>","DOI":"10.1093\/hmg\/ddac178","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T17:19:41Z","timestamp":1659633581000},"page":"4286-4294","source":"Crossref","is-referenced-by-count":11,"title":["A genome-wide association study for rheumatoid arthritis replicates previous HLA and non-HLA associations in a cohort from South Africa"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6746-2259","authenticated-orcid":false,"given":"Evans M","family":"Mathebula","sequence":"first","affiliation":[{"name":"University of the Witwatersrand Division of Human Genetics, School of Pathology and National Health Laboratory Services, Faculty of Health Sciences, , Johannesburg, 2000 , South Africa"},{"name":"University of the Witwatersrand Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, , Johannesburg, 2193 , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6315-7804","authenticated-orcid":false,"given":"Dhriti","family":"Sengupta","sequence":"additional","affiliation":[{"name":"University of the Witwatersrand Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, , Johannesburg, 2193 , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimmisha","family":"Govind","sequence":"additional","affiliation":[{"name":"University of the Witwatersrand Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, , Johannesburg, 2193 , South Africa"},{"name":"University of the Witwatersrand Division of Rheumatology, , Johannesburg, 1864 , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent A","family":"Laufer","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham (UAB) Division of Clinical Immunology and Rheumatology, , Birmingham, AL 35294 , USA"},{"name":"University of Alabama at Birmingham Medical Scientist Training Program (UAB MSTP) , Birmingham, AL 35294 , USA"},{"name":"University of Alabama at Birmingham Department of Medicine, , Birmingham, AL 35294 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3785-1389","authenticated-orcid":false,"given":"S Louis","family":"Bridges Jr","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine Department of Medicine, Hospital for Special Surgery, New York, NY, USA and Division of Rheumatology, , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Tikly","sequence":"additional","affiliation":[{"name":"University of the Witwatersrand Division of Rheumatology, , Johannesburg, 1864 , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4156-4801","authenticated-orcid":false,"given":"Mich\u00e8le","family":"Ramsay","sequence":"additional","affiliation":[{"name":"University of the Witwatersrand Division of Human Genetics, School of Pathology and National Health Laboratory Services, Faculty of Health Sciences, , Johannesburg, 2000 , South Africa"},{"name":"University of the Witwatersrand Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, , Johannesburg, 2193 , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8225-9531","authenticated-orcid":false,"given":"Ananyo","family":"Choudhury","sequence":"additional","affiliation":[{"name":"University of the Witwatersrand Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, , Johannesburg, 2193 , South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"key":"2022121720474001000_ref1","first-page":"1","article-title":"Epidemiology and genetics of rheumatoid arthritis","volume":"4","author":"Silman","year":"2002","journal-title":"Arthritis Res. Ther."},{"key":"2022121720474001000_ref2","first-page":"409","article-title":"Rheumatoid arthritis impact survey","volume":"74","author":"Mody","year":"1988","journal-title":"S. Afr. Med. J."},{"key":"2022121720474001000_ref3","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S1521-6942(03)00047-0","article-title":"Rheumatoid arthritis in the developing world","volume":"17","author":"Kalla","year":"2003","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"2022121720474001000_ref4","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature01661","article-title":"Evolving concepts of rheumatoid arthritis","volume":"423","author":"Firestein","year":"2003","journal-title":"Nature"},{"key":"2022121720474001000_ref5","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1002\/art.21575","article-title":"A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination","volume":"54","author":"Klareskog","year":"2006","journal-title":"Arthritis Rheum."},{"key":"2022121720474001000_ref6","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/art.24385","article-title":"Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis","volume":"60","author":"Woude","year":"2009","journal-title":"Arthritis Rheum."},{"key":"2022121720474001000_ref7","first-page":"404","article-title":"Rheumatic diseases in patients attending a clinic at a referral hospital in Yaounde, Cameroon","volume":"84","author":"Singwe-Ngandeu","year":"2007","journal-title":"East Afr. Med. J."},{"key":"2022121720474001000_ref8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1399-0039.1990.tb01813.x","article-title":"(1990) The association between HLA and rheumatoid artlmtis in Zimbabwean Blacks. The association between HLA and rheumatoid artlmtis in Zimbabwean Blacks","volume":"36","author":"Martell","year":"1990","journal-title":"Tissue Antigens"},{"key":"2022121720474001000_ref9","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/art.1780301102","article-title":"The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis","volume":"30","author":"Gregersen","year":"1987","journal-title":"Arthritis Rheum."},{"key":"2022121720474001000_ref10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3899\/jrheum.180107","article-title":"HLA-DRB1 Amino Acid Positions and Residues Associated with Antibody-positive Rheumatoid Arthritis in Black South Africans","volume":"46","author":"Govind","year":"2019","journal-title":"J. Rheumatol."},{"key":"2022121720474001000_ref11","doi-asserted-by":"crossref","first-page":"3274","DOI":"10.1002\/art.38855","article-title":"HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues","volume":"66","author":"Reynolds","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"2022121720474001000_ref12","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2119\/molmed.2014.00097","article-title":"Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthritis in black South Africans","volume":"20","author":"Govind","year":"2014","journal-title":"Mol. Med."},{"key":"2022121720474001000_ref13","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1093\/hmg\/ddy395","article-title":"Genetic influences on susceptibility to rheumatoid arthritis in African-Americans","volume":"28","author":"Laufer","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2022121720474001000_ref14","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1093\/rheumatology\/kep399","article-title":"The PTPN22 R620W polymorphism is not associated with systemic rheumatic diseases in South Africans","volume":"49","author":"Tikly","year":"2010","journal-title":"Rheumatology"},{"key":"2022121720474001000_ref15","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nature06258","article-title":"A second generation human haplotype map of over 3.1 million SNPs","volume":"449","author":"International HapMap Consortium","year":"2007","journal-title":"Nature"},{"key":"2022121720474001000_ref16","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1056\/NEJMoa073491","article-title":"TRAF1-C5 as a risk locus for rheumatoid arthritis \u2013 a genomewide study","volume":"357","author":"Plenge","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"2022121720474001000_ref17","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1002\/art.21123","article-title":"Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn\u2019s disease, in Canadian populations","volume":"52","author":"Oene","year":"2005","journal-title":"Arthritis Rheum."},{"key":"2022121720474001000_ref18","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.arcmed.2015.05.011","article-title":"Associations between PADI4 gene polymorphisms and rheumatoid arthritis: an updated meta-analysis","volume":"46","author":"Yang","year":"2015","journal-title":"Arch. Med. Res."},{"key":"2022121720474001000_ref19","doi-asserted-by":"crossref","first-page":"707690","DOI":"10.3389\/fimmu.2021.707690","article-title":"PADI4 polymorphisms confer risk of anti-CCP-positive rheumatoid arthritis in synergy with HLA-DRB1*04 and smoking","volume":"12","author":"Massarenti","year":"2021","journal-title":"Front. Immunol."},{"key":"2022121720474001000_ref20","first-page":"195","article-title":"Rheumatoid arthritis: a female challenge","volume":"4","author":"Gerosa","year":"2008","journal-title":"Womens Health"},{"key":"2022121720474001000_ref21","doi-asserted-by":"crossref","first-page":"648","DOI":"10.7196\/SAMJnew.7932","article-title":"Prevalence of tobacco use among adults in South Africa: results from the first South African National Health and Nutrition Examination Survey","volume":"105","author":"Reddy","year":"2015","journal-title":"S. Afr. Med. J."},{"key":"2022121720474001000_ref22","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","article-title":"GCTA: a tool for genome-wide complex trait analysis","volume":"88","author":"Yang","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2022121720474001000_ref23","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1038\/s41588-021-00935-7","article-title":"A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response","volume":"53","author":"Luo","year":"2021","journal-title":"Nat. Genet."},{"key":"2022121720474001000_ref24","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"1000 Genomes Project Consortium","year":"2015","journal-title":"Nature"},{"key":"2022121720474001000_ref25","doi-asserted-by":"crossref","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2022121720474001000_ref26","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1136\/annrheumdis-2020-219065","article-title":"Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci","volume":"80","author":"Ha","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"2022121720474001000_ref27","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s41586-020-2859-7","article-title":"High-depth African genomes inform human migration and health","volume":"586","author":"Choudhury","year":"2020","journal-title":"Nature"},{"key":"2022121720474001000_ref28","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1038\/s41467-021-22207-y","article-title":"Genetic substructure and complex demographic history of South African Bantu speakers","volume":"12","author":"Sengupta","year":"2021","journal-title":"Nat. Commun."},{"key":"2022121720474001000_ref29","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1126\/science.aal1988","article-title":"Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America","volume":"356","author":"Patin","year":"2017","journal-title":"Science"},{"key":"2022121720474001000_ref30","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.jid.2018.07.044","article-title":"NEDD4 is involved in inflammation development during keloid formation","volume":"139","author":"Fujita","year":"2019","journal-title":"J. Invest. Dermatol."},{"key":"2022121720474001000_ref31","doi-asserted-by":"crossref","first-page":"4330","DOI":"10.1038\/s41467-019-12026-7","article-title":"The transferability of lipid loci across African, Asian and European cohorts","volume":"10","author":"Kuchenbaecker","year":"2019","journal-title":"Nat. Commun."},{"key":"2022121720474001000_ref32","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1097\/BOR.0000000000000452","article-title":"Rheumatoid arthritis and citrullination","volume":"30","author":"Darrah","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"2022121720474001000_ref33","article-title":"H3Africa AWI-Gen Collaborative Centre: a resource to study the interplay between genomic and environmental risk factors for cardiometabolic diseases in four sub-Saharan African countries","volume":"1","author":"Ramsay","year":"2016","journal-title":"Global Health Epidemiol Genom"},{"key":"2022121720474001000_ref34","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"2022121720474001000_ref35","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.0020190","article-title":"Population structure and eigenanalysis","volume":"2","author":"Patterson","year":"2006","journal-title":"PLoS Genet."},{"key":"2022121720474001000_ref36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"2022121720474001000_ref37","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"2022121720474001000_ref38","doi-asserted-by":"crossref","DOI":"10.1101\/005165","article-title":"qqman: an R package for visualizing GWAS results using Q-Q and manhattan plots","volume-title":"Journal of Open Source Software","author":"Turner"},{"key":"2022121720474001000_ref39","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.0006-341X.1999.00997.x","article-title":"Genomic control for association studies","volume":"55","author":"Devlin","year":"1999","journal-title":"Biometrics"},{"key":"2022121720474001000_ref40","doi-asserted-by":"crossref","first-page":"S88","DOI":"10.1002\/gepi.20478","article-title":"Population stratification and patterns of linkage disequilibrium","volume":"33","author":"Hinrichs","year":"2009","journal-title":"Genet. Epidemiol."},{"key":"2022121720474001000_ref41","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"2022121720474001000_ref42","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat. Commun."},{"key":"2022121720474001000_ref43","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","article-title":"LocusZoom: regional visualization of genome-wide association scan results","volume":"26","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"2022121720474001000_ref44","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.ajhg.2011.04.014","article-title":"Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies","volume":"88","author":"Han","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2022121720474001000_ref45","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s00296-020-04731-0","article-title":"The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review","volume":"41","author":"Almutairi","year":"2021","journal-title":"Rheumatol. Int."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddac178\/45600461\/ddac178.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/24\/4286\/47999951\/ddac178.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/24\/4286\/47999951\/ddac178.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T20:48:10Z","timestamp":1671310090000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/24\/4286\/6655855"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,4]]},"references-count":45,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,8,4]]},"published-print":{"date-parts":[[2022,12,16]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddac178","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,15]]},"published":{"date-parts":[[2022,8,4]]}}}