{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T13:50:30Z","timestamp":1767016230411,"version":"3.40.5"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Observational studies have suggested a relationship between type-1 diabetes mellitus (T1DM) and systemic lupus erythematosus (SLE). In both autoimmunities, 25-hydroxyvitamin D (25-OHD) deficiency is common. However, the causality between T1DM, 25-OHD level and SLE remains largely unknown.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>Independent genetic variants associated with T1DM, 25-OHD level, and SLE from the largest genome-wide association studies were used to conduct two-sample bidirectional Mendelian randomization (BIMR) and two-step Mendelian randomization (MR) analysis to estimate causal relationship between T1DM, 25-OHD level and SLE, and further multivariable Mendelian randomization (MVMR) was used to verify direct causality of T1DM and 25-OHD level on SLE. A series of sensitivity analysis as validation of primary MR results were performed.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>Consistent with the results of BIMR, there was strong evidence for a direct causal effect of T1DM on the risk of SLE (OR<jats:sub>MVMR-IVW<\/jats:sub>= 1.249, 95% CI = 1.148\u20131.360,<jats:italic>P<\/jats:italic><jats:sub>MVMR-IVW<\/jats:sub>= 1.25\u00d710<jats:sup>\u22125<\/jats:sup>), and 25-OHD level was negatively associated with the risk of SLE (OR<jats:sub>MVMR-IVW<\/jats:sub>= 0.305, 95% CI = 0.109\u20130.857,<jats:italic>P<\/jats:italic><jats:sub>MVMR-IVW<\/jats:sub>= 0.031). We also observed a negative causal effect of T1DM on 25-OHD level (OR<jats:sub>BIMR-IVW<\/jats:sub>= 0.995, 95% CI = 0.991\u20130.999,<jats:italic>P<\/jats:italic><jats:sub>BIMR-IVW<\/jats:sub>= 0.030) while the causal effect of 25-OHD level on the risk of T1DM did not exist (<jats:italic>P<\/jats:italic><jats:sub>BIMR-IVW<\/jats:sub>= 0.106). In BIMR analysis, there was no evidence for causal effects of SLE on the risk of T1DM and 25-OHD level (<jats:italic>P<\/jats:italic><jats:sub>BIMR-IVW<\/jats:sub>&gt; 0.05, respectively).<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusion<\/jats:title><jats:p>Our MR analysis suggested that there was a network causal relationship between T1DM, 25-OHD level and SLE. T1DM and 25-OHD level both have causal associations with the risk of SLE, and 25-OHD level could be a mediator in the causality of T1DM and SLE.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0285915","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T17:27:42Z","timestamp":1684344462000},"page":"e0285915","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["A network causal relationship between type-1 diabetes mellitus, 25-hydroxyvitamin D level and systemic lupus erythematosus: Mendelian randomization study"],"prefix":"10.1371","volume":"18","author":[{"given":"Kaisheng","family":"Su","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhifang","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhua","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanlin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenyu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0174-9174","authenticated-orcid":true,"given":"Jing","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"issue":"1","key":"pone.0285915.ref001","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/1756-185X.13089","article-title":"Hashimoto thyroiditis, anti-thyroid antibodies and systemic lupus erythematosus","volume":"21","author":"RT Posselt","year":"2018","journal-title":"Int J Rheum Dis"},{"issue":"11","key":"pone.0285915.ref002","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1177\/0961203308091539","article-title":"Diabetes mellitus complicating systemic lupus erythematosus\u2014analysis of the UCL lupus cohort and review of the literature","volume":"17","author":"S Cortes","year":"2008","journal-title":"Lupus"},{"issue":"12","key":"pone.0285915.ref003","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/nrrheum.2016.186","article-title":"New insights into the immunopathogenesis of systemic lupus erythematosus","volume":"12","author":"GC Tsokos","year":"2016","journal-title":"Nat Rev Rheumatol"},{"key":"pone.0285915.ref004","doi-asserted-by":"crossref","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"A Katsarou","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"3","key":"pone.0285915.ref005","first-page":"326","article-title":"Mixed connective tissue disease-enigma variations?","volume":"56","author":"NC Ciang","year":"2017","journal-title":"Rheumatology (Oxford)"},{"issue":"7","key":"pone.0285915.ref006","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.3390\/nu12072097","article-title":"Immunologic Effects of Vitamin D on Human Health and Disease","volume":"12","author":"N Charoenngam","year":"2020","journal-title":"Nutrients"},{"issue":"5","key":"pone.0285915.ref007","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S2213-8587(23)00060-8","article-title":"Vitamin D: 100 years of discoveries, yet controversy continues","volume":"11","author":"JC Gallagher","year":"2023","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"19","key":"pone.0285915.ref008","doi-asserted-by":"crossref","first-page":"10659","DOI":"10.3390\/ijms221910659","article-title":"Vitamin D and Rheumatic Diseases: A Review of Clinical Evidence","volume":"22","author":"N. 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