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The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti\u2013carbamylated protein antibody\u2013positive (anti\u2010CarP+) RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Analyses were restricted to RA patients who were anti\u2013cyclic citrullinated peptide antibody negative (anti\u2010CCP\u2212), because the anti\u2010CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti\u2010CCP\u2212 RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti\u2010CarP status in RA patients was tested with logistic regression and combined with inverse\u2010variance meta\u2010analysis. Significance of the associations was assessed according to a study\u2010specific threshold of <jats:italic>P<\/jats:italic> &lt; 2.0 \u00d7 10<jats:sup>\u22125<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The <jats:italic>HLA\u2013B*08<\/jats:italic> allele and its correlated amino acid variant Asp\u20109 showed a significant association with anti\u2010CarP+\/anti\u2010CCP\u2212 RA (<jats:italic>P<\/jats:italic> &lt; 3.78 \u00d7 10<jats:sup>\u22127<\/jats:sup>; I<jats:sup>2<\/jats:sup> = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti\u2010CarP\u2212\/anti\u2010CCP\u2212 RA patients, and anti\u2010CCP\u2212 RA patients who were positive for other anti\u2013citrullinated protein antibodies. Based on these findings, anti\u2010CarP+\/anti\u2010CCP\u2212 RA patients could be separated from other antibody\u2010defined subsets of RA patients in whom an association with the <jats:italic>HLA\u2013B*08<\/jats:italic> allele has been previously demonstrated. No other MHC variant remained associated with anti\u2010CarP+\/anti\u2010CCP\u2212 RA after accounting for the presence of the <jats:italic>HLA\u2013B*08<\/jats:italic> allele. Specifically, the reported association of <jats:italic>HLA\u2013DRB1*03<\/jats:italic> was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results identify <jats:italic>HLA\u2013B*08<\/jats:italic> carrying Asp\u20109 as the MHC locus showing the strongest association with anti\u2010CarP+\/anti\u2010CCP\u2212 RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41630","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T04:53:36Z","timestamp":1609390416000},"page":"963-969","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["<i>HLA\u2013B*08<\/i> Identified as the Most Prominently Associated Major Histocompatibility Complex Locus for Anti\u2013Carbamylated Protein Antibody\u2013Positive\/Anti\u2013Cyclic Citrullinated Peptide\u2013Negative Rheumatoid Arthritis"],"prefix":"10.1002","volume":"73","author":[{"given":"Cristina","family":"Regueiro","sequence":"first","affiliation":[{"name":"Instituto de Investigacion Sanitaria and Hospital Cl\u00ednico Universitario de Santiago  Santiago de Compostela 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Biomedicina L\u00f3pez\u2010Neyra IPBLN\u2010CSIC  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2869-7861","authenticated-orcid":false,"given":"Luis","family":"Rodriguez\u2010Rodriguez","sequence":"additional","affiliation":[{"name":"Hospital Cl\u00ednico San Carlos Instituto Investigaci\u00f3n Sanitaria San Carlos  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Lopez\u2010Mejias","sequence":"additional","affiliation":[{"name":"Valdecilla Biomedical Research Institute, Hospital Universitario Marqu\u00e9s de Valdecilla IDIVAL  Santander Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Perez\u2010Pampin","sequence":"additional","affiliation":[{"name":"Instituto de Investigacion Sanitaria and Hospital Cl\u00ednico Universitario de Santiago  Santiago de Compostela 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