{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:49:42Z","timestamp":1791269382119,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2007,4,27]],"date-time":"2007-04-27T00:00:00Z","timestamp":1177632000000},"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":[[2007,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address these issues, a nationwide case\u2013control study was conducted in Denmark during 2002\u20132004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex\u2010 and age\u2010matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti\u2010CCP\u2013positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8\u201329.4) but not anti\u2010CCP\u2013negative RA (OR 1.07, 95% CI 0.53\u20132.18). Strong combined gene\u2013environment effects were observed, with markedly increased risks of anti\u2010CCP\u2013positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0\u2013154), heavy coffee drinkers (OR 53.3, 95% CI 15.5\u2013183), or oral contraceptive users (OR 44.6, 95% CI 15.2\u2013131) compared with SE noncarriers who were not exposed to these environmental risk factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti\u2010CCP\u2013positive RA. A distinction between anti\u2010CCP\u2013positive RA and anti\u2010CCP\u2013negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.22597","type":"journal-article","created":{"date-parts":[[2007,4,27]],"date-time":"2007-04-27T17:46:25Z","timestamp":1177695985000},"page":"1446-1453","source":"Crossref","is-referenced-by-count":172,"title":["Strong combined gene\u2013environment effects in anti\u2013cyclic citrullinated peptide\u2013positive rheumatoid arthritis: A nationwide case\u2013control study in Denmark"],"prefix":"10.1002","volume":"56","author":[{"given":"Merete","family":"Pedersen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Jacobsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Garred","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans O.","family":"Madsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Klarlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Svejgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo V.","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Wohlfahrt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Frisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,4,27]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar568"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21385"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar2022"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780310302"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197804202981602"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.3109\/08916939709003856"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780370510"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/ar1187"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21302"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20553"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21575"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.041079"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.314.7083.775"},{"key":"e_1_2_7_15_2","first-page":"1069","article-title":"Socio\u2010economic status and risk of rheumatoid arthritis: a Danish case\u2010control study","volume":"33","author":"Pedersen M","year":"2006","journal-title":"J Rheumatol"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008390-199201000-00012"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2005.09.005"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0198-8859(00)00114-2"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a114174"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.59.8.631"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200201)46:1<83::AID-ART10042>3.0.CO;2-D"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a008846"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.2.538"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.49.12.980"},{"key":"e_1_2_7_25_2","first-page":"525","article-title":"Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis","volume":"5","author":"Voigt LF","year":"1994","journal-title":"Epidemiology"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1986.03380110080031"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.schbul.a033407"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0920-9964(96)82950-1"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20001204)96:6<870::AID-AJMG36>3.0.CO;2-L"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.1176\/ajp.153.12.1530"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.21419"}],"container-title":["Arthritis &amp; 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