{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T02:30:28Z","timestamp":1788316228165,"version":"build-2803163510"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009881","name":"Juvenile Diabetes Research Foundation Canada","doi-asserted-by":"publisher","award":["3-PDF-2017-370-A-N:"],"award-info":[{"award-number":["3-PDF-2017-370-A-N:"]}],"id":[{"id":"10.13039\/100009881","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de Recherche du Qu\u00e9bec - Sant\u00e9","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol\/l change in 25OHD levels in vitamin D\u2013insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, <jats:italic>p<\/jats:italic> = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1003536","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T18:28:13Z","timestamp":1614277693000},"page":"e1003536","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":69,"title":["Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4133-0618","authenticated-orcid":true,"given":"Despoina","family":"Manousaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2616-7274","authenticated-orcid":true,"given":"Adil","family":"Harroud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3506-160X","authenticated-orcid":true,"given":"Ruth E.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6061-4720","authenticated-orcid":true,"given":"Vince","family":"Forgetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7141-9189","authenticated-orcid":true,"given":"Nicholas J.","family":"Timpson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-8314","authenticated-orcid":true,"given":"George Davey","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Polychronakos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3746-9086","authenticated-orcid":true,"given":"J Brent","family":"Richards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"issue":"1","key":"pmed.1003536.ref001","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/dmrr.1141","article-title":"The changing epidemiology of type 1 diabetes: why is it going through the roof?","volume":"27","author":"K Vehik","year":"2011","journal-title":"Diabetes Metab Res Rev"},{"issue":"3","key":"pmed.1003536.ref002","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s00125-004-1329-3","article-title":"Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice","volume":"47","author":"A Giulietti","year":"2004","journal-title":"Diabetologia"},{"issue":"6","key":"pmed.1003536.ref003","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1007\/BF00403372","article-title":"Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3","volume":"37","author":"C Mathieu","year":"1994","journal-title":"Diabetologia"},{"issue":"2","key":"pmed.1003536.ref004","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1046\/j.1365-2249.1998.00568.x","article-title":"1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes","volume":"112","author":"K Casteels","year":"1998","journal-title":"Clin Exp Immunol"},{"key":"pmed.1003536.ref005","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/j.1749-6632.2003.tb06057.x","article-title":"Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting autoimmune diabetes","volume":"987","author":"L. 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