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Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (<jats:italic>n<\/jats:italic> = 159) were classified according to predefined criteria. Controls (<jats:italic>n<\/jats:italic> = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based <jats:italic>HLA-DRB1<\/jats:italic> and <jats:italic>HLA-DQB1<\/jats:italic> genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish <jats:italic>DRB1*04<\/jats:italic> subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of <jats:italic>HLA-DRB1<\/jats:italic> and <jats:italic>HLA-DQB1<\/jats:italic> alleles between patients with ExRA and controls. <jats:italic>DRB1*0401<\/jats:italic> (<jats:italic>P<\/jats:italic> = 0.003) and <jats:italic>0401<\/jats:italic>\/<jats:italic>0401<\/jats:italic> homozygosity (<jats:italic>P<\/jats:italic> = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two <jats:italic>HLA-DRB1*04<\/jats:italic> alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04\u20133.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22\u20134.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with <jats:italic>HLA-DRB1*0401<\/jats:italic>. Other ExRA manifestations were not associated with individual alleles but with <jats:italic>DRB1*04<\/jats:italic> SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.<\/jats:p>","DOI":"10.1186\/ar1837","type":"journal-article","created":{"date-parts":[[2005,10,11]],"date-time":"2005-10-11T18:14:25Z","timestamp":1129054465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["The impact of HLA-DRB1genes on extra-articular disease manifestations in rheumatoid arthritis"],"prefix":"10.1186","volume":"7","author":[{"given":"Carl","family":"Turesson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J","family":"Schaid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia M","family":"Weyand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lennart TH","family":"Jacobsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg J","family":"Goronzy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingemar F","family":"Petersson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunnar","family":"Sturfelt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britt-Marie","family":"Nyh\u00e4ll-W\u00e5hlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lennart","family":"Truedsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja A","family":"Dechant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric L","family":"Matteson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2005,10,11]]},"reference":[{"key":"1715_CR1","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/0002-9343(73)90040-5","volume":"54","author":"DA Gordon","year":"1973","unstructured":"Gordon DA, Stein JL, Broder I: The extra-articular features of rheumatoid arthritis. 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