{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:34:21Z","timestamp":1770834861580,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, <jats:italic>P<\/jats:italic>\u00a0<jats:sub>IVW-FE<\/jats:sub> = 1.01 \u00d7 10<jats:sup>-21<\/jats:sup>), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, <jats:italic>P<\/jats:italic><jats:sub>IVW-MRE<\/jats:sub> = 9.88 \u00d7 10<jats:sup>-2<\/jats:sup>). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All <jats:italic>P<\/jats:italic> &amp;lt; 6.25 \u00d7 10<jats:sup>-3<\/jats:sup>). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (<jats:italic>P<\/jats:italic> &amp;lt; 6.25 \u00d7 10<jats:sup>-3<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1325127","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T04:32:15Z","timestamp":1713760335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The causal relationship between sarcoidosis and autoimmune diseases: a bidirectional Mendelian randomization study in FinnGen"],"prefix":"10.3389","volume":"15","author":[{"given":"Di","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruimin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiao","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41572-019-0096-x","article-title":"Sarcoidosis","volume":"5","author":"Grunewald","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1701815","DOI":"10.1183\/13993003.01815-2017","article-title":"Sarcoidosis mortality in Sweden: a population-based cohort study","volume":"51","author":"Rossides","year":"2018","journal-title":"Eur Respir J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201707-564OT","article-title":"Disease burden and variability in sarcoidosis","volume":"14","author":"Gerke","year":"2017","journal-title":"Ann Am Thorac Soc"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2018.03.028","article-title":"Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003-2015: A nationwide population-based study","author":"Park","year":"2018","journal-title":"Respir Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13629","article-title":"Sarcoidosis: Epidemiology and clinical insights","volume":"293","author":"Rossides","year":"2023","journal-title":"J Intern Med"},{"key":"B6","article-title":"The frequency of sarcoidosis in Finland and Hokkaido, Japan. A comparative epidemiological study","volume":"12","author":"Pietinalho","year":"1995","journal-title":"Sarcoidosis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201511-760OC","article-title":"Sarcoidosis in america. Analysis based on health care use","volume":"13","author":"Baughman","year":"2016","journal-title":"Ann Am Thorac Soc"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1900444","DOI":"10.1183\/13993003.00444-2019","article-title":"Epidemiology and health outcomes of sarcoidosis in a universal healthcare population: a cohort study","volume":"54","author":"Fidler","year":"2019","journal-title":"Eur Respir J"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445-5994.2007.01365.x","article-title":"Sarcoidosis in Australia","volume":"37","author":"Gillman","year":"2007","journal-title":"Intern Med J"},{"key":"B10","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s12931-018-0871-3","article-title":"Prevalence and incidence of sarcoidosis in Korea: a nationwide population-based study","volume":"19","author":"Yoon","year":"2018","journal-title":"Respir Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-014-8414-2","article-title":"Unmet needs in autoimmunity and potential new tools","volume":"47","author":"Lu","year":"2014","journal-title":"Clin Rev Allergy Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1427-3","article-title":"Familial association between type 1 diabetes and other autoimmune and related diseases","volume":"52","author":"Hemminki","year":"2009","journal-title":"Diabetologia"},{"key":"B13","doi-asserted-by":"publisher","first-page":"465,467","DOI":"10.1001\/archinte.157.4.465","article-title":"Association of sarcoidosis, insulin-dependent diabetes mellitus, and ulcerative colitis","volume":"157","author":"Yoshioka","year":"1997","journal-title":"Arch Intern Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/j.cgh.2015.01.026","article-title":"Autoimmune disease in first-degree relatives and spouses of individuals with celiac disease","volume":"13","author":"Emilsson","year":"2015","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/jebm.12355","article-title":"Celiac disease and risk of sarcoidosis: A systematic review and meta-analysis","volume":"12","author":"Wijarnpreecha","year":"2019","journal-title":"J Evid Based Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1378\/chest.06-1074","article-title":"Thoracic manifestations of inflammatory bowel disease","volume":"131","author":"Black","year":"2007","journal-title":"Chest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00160310","article-title":"Genetic commonality between inflammatory bowel disease and sarcoidosis: the beginning of the end or the end of the beginning","volume":"37","author":"Cerri","year":"2011","journal-title":"Eur Respir J"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i33.6137","article-title":"Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases","volume":"23","author":"Halling","year":"2017","journal-title":"World J Gastroenterol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/MCP.0000000000000809","article-title":"Sarcoidosis and autoimmunity","volume":"27","author":"Song","year":"2021","journal-title":"Curr Opin Pulm Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"\u2018Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease","volume":"32","author":"Smith","year":"2003","journal-title":"Int J Epidemiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2015.08.001","article-title":"Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors","volume":"69","author":"Burgess","year":"2016","journal-title":"J Clin Epidemiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Davey Smith","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1177\/0962280206077743","article-title":"Mendelian randomization as an instrumental variable approach to causal inference","volume":"16","author":"Didelez","year":"2007","journal-title":"Stat Methods Med Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw373","article-title":"PhenoScanner: a database of human genotype-phenotype associations","volume":"32","author":"Staley","year":"2016","journal-title":"Bioinformatics"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz469","article-title":"PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations","volume":"35","author":"Kamat","year":"2019","journal-title":"Bioinformatics"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat Genet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1055953","article-title":"Low vitamin D concentrations and BMI are causal factors for primary biliary cholangitis: A mendelian randomization study","volume":"13","author":"Xu","year":"2022","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-022-01412-9","article-title":"Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression","volume":"6","author":"Yao","year":"2022","journal-title":"Nat Hum Behav"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1177\/0962280210394459","article-title":"Using multiple genetic variants as instrumental variables for modifiable risk factors","volume":"21","author":"Palmer","year":"2012","journal-title":"Stat Methods Med Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21965","article-title":"Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator","volume":"40","author":"Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7221","article-title":"A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization","volume":"36","author":"Bowden","year":"2017","journal-title":"Stat Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyy258","article-title":"Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption","volume":"48","author":"Bowden","year":"2019","journal-title":"Int J Epidemiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy163","article-title":"Evaluating the potential role of pleiotropy in Mendelian randomization studies","volume":"27","author":"Hemani","year":"2018","journal-title":"Hum Mol Genet"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS summary data","volume":"13","author":"Hemani","year":"2017","journal-title":"PloS Genet"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"Elife"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.13654","article-title":"Comorbid autoimmune diseases in patients with sarcoidosis: A nationwide case-control study in Taiwan","volume":"44","author":"Wu","year":"2017","journal-title":"J Dermatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.46497\/ArchRheumatol.2020.7649","article-title":"Concomitant autoimmune diseases in patients with sarcoidosis in Turkey","volume":"35","author":"Yildiz","year":"2020","journal-title":"Arch Rheumatol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2021.105236","article-title":"Coexistence of immune-mediated diseases in sarcoidosis. Frequency and clinical significance in 1737 patients","volume":"88","author":"Brito-Zeron","year":"2021","journal-title":"Joint Bone Spine"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.021532018","article-title":"Moving target: shifting the focus to pulmonary sarcoidosis as an autoimmune spectrum disorder","volume":"54","author":"Kaiser","year":"2019","journal-title":"Eur Respir J"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.1996.0026","article-title":"T cell-mediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases","volume":"9","author":"Sakaguchi","year":"1996","journal-title":"J Autoimmun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.59","article-title":"Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens","volume":"11","author":"Koning","year":"2015","journal-title":"Nat Rev Rheumatol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.autrev.2013.06.004","article-title":"Innate and adaptive immunity in inflammatory bowel disease","volume":"13","author":"Geremia","year":"2014","journal-title":"Autoimmun Rev"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3643","article-title":"A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases","volume":"18","author":"Liang","year":"2017","journal-title":"Nat Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1325127\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T04:32:20Z","timestamp":1713760340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1325127\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,22]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2024.1325127"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1325127","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,22]]},"article-number":"1325127"}}