{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:32:23Z","timestamp":1791091943475,"version":"4.1.0"},"reference-count":15,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,3,30]],"date-time":"2009-03-30T00:00:00Z","timestamp":1238371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The co\u2010occurrence of different autoimmune diseases in patients and their families suggests the presence of shared genetic risk factors. Two compelling candidate autoimmune disease susceptibility genes are those that encode CTLA4 and inducible costimulator (ICOS), immunoregulatory proteins. Associations of <jats:italic>CTLA4<\/jats:italic> polymorphisms with various autoimmune diseases have been reported, but for rheumatoid arthritis (RA) and primary biliary cirrhosis (PBC), the association data are inconsistent and have largely excluded analysis of polymorphisms in the <jats:italic>ICOS<\/jats:italic> gene adjacent to <jats:italic>CTLA4<\/jats:italic>. We undertook this study to examine whether <jats:italic>CTLA4<\/jats:italic> and <jats:italic>ICOS<\/jats:italic> influence RA and PBC susceptibility by testing <jats:italic>CTLA4\/ICOS<\/jats:italic> polymorphisms for association with these diseases in Canadian subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Caucasian RA patients (n = 1,140), PBC patients (n = 481), and controls (n = 1,248) were typed for 21 biallelic polymorphisms across the <jats:italic>CTLA4\/ ICOS<\/jats:italic> genes using a multiplex genotyping array, and the results were analyzed using a false discovery rate method to correct for multiple testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significant associations of multiple <jats:italic>CTLA4<\/jats:italic> and <jats:italic>ICOS<\/jats:italic> gene polymorphisms with RA and PBC were observed, with the strongest association signals for both diseases coming from a <jats:italic>CTLA4\/ICOS<\/jats:italic> intergenic single\u2010nucleotide polymorphism, rs17268364 (corrected <jats:italic>P<\/jats:italic> [<jats:italic>P<\/jats:italic><jats:sub>corr<\/jats:sub>] = 6.0 \u00d7 10<jats:sup>\u20134<\/jats:sup> and <jats:italic>P<\/jats:italic><jats:sub>corr<\/jats:sub> &lt; 1.0 \u00d7 10<jats:sup>\u20134<\/jats:sup>, respectively). Significant associations, which were common to both diseases, were also observed with other alleles and haplotypes across 3 linkage disequilibrium blocks within the <jats:italic>CTLA4<\/jats:italic> gene, the intergenic region, and the <jats:italic>ICOS<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results provide evidence for RA and PBC association with the <jats:italic>CTLA4\/ICOS<\/jats:italic> locus and suggest that the risk allele(s) within this region may be common to both diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.24412","type":"journal-article","created":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T01:45:08Z","timestamp":1238463908000},"page":"931-937","source":"Crossref","is-referenced-by-count":63,"title":["<i>CTLA4\/ICOS<\/i> gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population"],"prefix":"10.1002","volume":"60","author":[{"given":"Erin J.","family":"Walker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon M.","family":"Hirschfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalina","family":"Coltescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kesheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Newman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Bykerk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward C.","family":"Keystone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne","family":"Mosher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher I.","family":"Amos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Jenny","family":"Heathcote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Siminovitch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,3,30]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hch078"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.rhu.0000099623.30805.2f"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2008.02.007"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken005"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1053\/he.2000.5984"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-005-0033-9"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/498651"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1080\/17402520500317859"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22048"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2007.02.012"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206894200"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706409104"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.20383"}],"container-title":["Arthritis &amp; Rheumatism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.24412","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.24412","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T12:12:29Z","timestamp":1696680749000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/art.24412"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,30]]},"references-count":15,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,4]]}},"alternative-id":["10.1002\/art.24412"],"URL":"https:\/\/doi.org\/10.1002\/art.24412","archive":["Portico"],"relation":{},"ISSN":["0004-3591","1529-0131"],"issn-type":[{"value":"0004-3591","type":"print"},{"value":"1529-0131","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,30]]}}}