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We examined the interaction effects of heavy smoking (&gt;10 pack\u2010years) and the genetic risk score (GRS) of multiple RA\u2010associated amino acid positions (positions 11, 13, 71, and 74 in HLA\u2013DR\u03b21, position 9 in HLA\u2013B, and position 9 in HLA\u2013DP\u03b21), as well as the interaction effects of heavy smoking and the GRS of HLA\u2013DR\u03b21 4\u2013amino acid haplotypes (assessed via attributable proportion due to interaction [AP] using the additive interaction model).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Heavy smoking and all investigated HLA amino acid positions and haplotypes were associated with RA susceptibility in the 3 populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA\u2013DR\u03b21 4\u2013amino acid haplotype (AP 0.416, 0.467, and 0.796, in the EIRA, NHS, and Korean studies, respectively). We further identified the key interacting variants as being located at HLA\u2013DR\u03b21 amino acid positions 11 and 13 but not at any of the other RA risk\u2013associated amino acid positions. For residues in positions 11 and 13, there were similar patterns between RA risk effects and interaction effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings of significant gene\u2013environment interaction effects indicate that a physical interaction between citrullinated autoantigens produced by smoking and HLA\u2013DR molecules is characterized by the HLA\u2013DR\u03b21 4\u2013amino acid haplotype, primarily by positions 11 and 13.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39228","type":"journal-article","created":{"date-parts":[[2015,6,22]],"date-time":"2015-06-22T10:46:55Z","timestamp":1434970015000},"page":"2611-2623","source":"Crossref","is-referenced-by-count":66,"title":["Interactions Between Amino Acid\u2013Defined Major Histocompatibility Complex Class II Variants and Smoking in Seropositive Rheumatoid Arthritis"],"prefix":"10.1002","volume":"67","author":[{"given":"Kwangwoo","family":"Kim","sequence":"first","affiliation":[{"name":"Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and Broad Institute Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Jiang","sequence":"additional","affiliation":[{"name":"Karolinska Institute Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Cui","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, and Broad Institute Cambridge  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Lu","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen H.","family":"Costenbader","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Sparks","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So\u2010Young","family":"Bang","sequence":"additional","affiliation":[{"name":"Hanyang University Hospital for Rheumatic Diseases Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye\u2010Soon","family":"Lee","sequence":"additional","affiliation":[{"name":"Hanyang University Hospital for Rheumatic Diseases Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinori","family":"Okada","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts, Tokyo Medical and Dental University, Tokyo, Japan, and RIKEN Center for Integrative Medical Sciences Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Raychaudhuri","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, Broad Institute, Cambridge, Massachusetts, and Manchester Academic Health Sciences Centre Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Alfredsson","sequence":"additional","affiliation":[{"name":"Karolinska Institute Stockholm 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