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This study was aimed at elucidating the genetics underlying these common features.<\/jats:p><\/jats:sec>Methods<\/jats:title>We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune\u2010related genes in a large cohort of 2,292 well\u2010characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene\u2010based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments.<\/jats:p><\/jats:sec>Results<\/jats:title>Case\u2013control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case\u2013case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti\u2013double\u2010stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual\u2010specificity phosphatase 1 (DUSP1<\/jats:italic>) protective genetic variants lead to increased gene expression and potentially to anti\u2010inflammatory effects on the SIAD\u2010associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down\u2010regulation of the MAPK signaling\u2010related gene DUSP1<\/jats:italic> in other skin disorders.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42988","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T13:39:52Z","timestamp":1726580392000},"page":"212-225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune 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