{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T06:48:45Z","timestamp":1785739725810,"version":"3.56.0"},"reference-count":46,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["DP2AI164325"],"award-info":[{"award-number":["DP2AI164325"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["U01HG012041"],"award-info":[{"award-number":["U01HG012041"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease characterized by clinical and molecular heterogeneity, notably in the presence of anti\u2013cyclic citrullinated peptide (CCP) antibodies. Patients with CCP+ RA exhibit more severe disease progression and distinct treatment responses compared to patients with CCP\u2212 RA. Although previous studies have investigated cellular and molecular differences between these subtypes, their genetic differences are understudied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We leveraged the Rheumatoid Arthritis Comparative Effectiveness Research cohort, comprising 555 patients with CCP+\/rheumatoid factor (RF)+ RA and 384 patients with CCP\u2212\/RF+ RA. Using a novel framework, we integrated a network\u2010based genome\u2010wide association study (GWAS) with multiomic data to uncover corresponding genetic and molecular differences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We uncovered a significant heritability difference between these disease groups. Network\u2010based GWAS uncovered 14 putative gene modules, including many genes outside the HLA loci, that explained genetic differences between CCP+\/RF+ and CCP\u2212\/RF+ RA. Heritability partitioning and multivariate expression analyses validated four modules, highlighting novel genetic loci underlying phenotypic differences. Module functional significance was established using multiple orthogonal cohorts, underscoring their biologic relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate the use of network\u2010based approaches in revealing differential genetic risk factors underlying CCP+\/RF+ and CCP\u2212\/RF+ RA. Disease\u2010associated gene modules detected in synovial tissue were also observed in peripheral blood, indicating joint\u2010specific molecular programs are reflected systemically. This cross\u2010tissue concordance highlights the potential for blood\u2010based assays to capture pathogenic mechanisms active in the joints, enabling practical patient stratification. Our findings highlight why patients with CCP+\/RF+ and CCP\u2212\/RF+ RA exhibit distinct clinical courses and therapeutic responses, supporting precision\u2010guided treatment strategy development in RA.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70091-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  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