{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T22:49:02Z","timestamp":1783118942501,"version":"3.54.6"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Evidence from observational studies on the association of folate and vitamin B<jats:sub>12<\/jats:sub>with autoimmune diseases are conflicting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We aimed to investigate the relationship of folate and vitamin B<jats:sub>12<\/jats:sub>with autoimmune diseases using Mendelian randomization (MR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We selected single-nucleotide polymorphisms associated with folate and vitamin B<jats:sub>12<\/jats:sub>at the genome-wide significance level. Summary-level data for four common autoimmune diseases (vitiligo, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus) were obtained from large-scale genome-wide association studies, with a sample size of 44,266, 86,640, 58,284, and 23,210, respectively. MR analyses were conducted using the inverse variance weighted (IVW) approach, and sensitivity analyses were further performed to test the robustness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that a higher genetically determined serum folate level per one standard deviation (SD) was associated with a decreased risk of vitiligo by the IVW method [odds ratios (OR) = 0.47; 95% confidence interval (CI): 0.32\u20130.69;<jats:italic>P<\/jats:italic>= 1.33 \u00d7 10<jats:sup>-4<\/jats:sup>]. Sensitivity analyses using alternative methods showed similar associations, and no evidence of pleiotropy was detected by MR-Egger regression (<jats:italic>P<\/jats:italic>= 0.919). In addition, we observed that vitamin B<jats:sub>12<\/jats:sub>per one SD was positively associated with IBD (IVW: OR = 1.14, 95% CI: 1.03\u20131.26,<jats:italic>P<\/jats:italic>= 0.010; maximum likelihood: OR = 1.14, 95% CI: 1.01\u20131.29,<jats:italic>P<\/jats:italic>= 0.035; MR-PRESSO: OR = 1.14, 95% CI:1.01\u20131.28,<jats:italic>P<\/jats:italic>=0.037), while the association was not significant after Bonferroni correction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The study provides convincing evidence for an inverse association between serum folate level and risk of vitiligo. Further studies are warranted to elucidate the possible association between vitamin B<jats:sub>12<\/jats:sub>and risk of IBD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1139799","type":"journal-article","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T05:16:14Z","timestamp":1678425374000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Genetically predicted levels of folate, vitamin B12, and risk of autoimmune diseases: A Mendelian randomization study"],"prefix":"10.3389","volume":"14","author":[{"given":"Hong","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aole","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linshuoshuo","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ding","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwv292","article-title":"Prediction and prevention of autoimmune disease in the 21st century: A review and preview","volume":"183","author":"Rose","year":"2016","journal-title":"Am J Epidemiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"312","DOI":"10.3892\/etm.2021.9743","article-title":"Novel immunological and genetic factors associated with vitiligo: A review","volume":"21","author":"Said-Fernandez","year":"2021","journal-title":"Exp Ther Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9","article-title":"Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: A systematic analysis for the global burden of disease study 2019","volume":"396","author":"Diseases","year":"2020","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30237-5","article-title":"Management strategies and future directions for systemic lupus erythematosus in adults","volume":"393","author":"Durcan","year":"2019","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/17474124.2019.1574569","article-title":"Extraintestinal manifestations in inflammatory bowel disease - epidemiology, genetics, and pathogenesis","volume":"13","author":"Greuter","year":"2019","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/nu12092867","article-title":"B vitamins and one-carbon metabolism: Implications in human health and disease","volume":"12","author":"Lyon","year":"2020","journal-title":"Nutrients"},{"key":"B8","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.jaad.2018.08.029","article-title":"Serum homocysteine, folate, and vitamin B(12) levels in patients with vitiligo and their potential roles as disease activity biomarkers: A systematic review and meta-analysis","volume":"80","author":"Tsai","year":"2019","journal-title":"J Am Acad Dermatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/07315724.2020.1788472","article-title":"Serum homocysteine, folate, and vitamin B(12) levels in patients with systemic lupus erythematosus: A meta-analysis and meta-regression","volume":"40","author":"Tsai","year":"2021","journal-title":"J Am Coll Nutr"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/nu9040382","article-title":"Associations between folate and vitamin B12 levels and inflammatory bowel disease: A meta-analysis","volume":"9","author":"Pan","year":"2017","journal-title":"Nutrients"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"Jama"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3680","article-title":"Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants","volume":"48","author":"Jin","year":"2016","journal-title":"Nat Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3359","article-title":"Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations","volume":"47","author":"Liu","year":"2015","journal-title":"Nat Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nature12873","article-title":"Genetics of rheumatoid arthritis contributes to biology and drug discovery","volume":"506","author":"Okada","year":"2014","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3434","article-title":"Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus","volume":"47","author":"Bentham","year":"2015","journal-title":"Nat Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003530","article-title":"Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets","volume":"9","author":"Grarup","year":"2013","journal-title":"PloS Genet"},{"key":"B17","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":"B18","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":"B19","doi-asserted-by":"publisher","first-page":"R195","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":"B20","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":"B21","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":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3538","article-title":"Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat Genet"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaad.2016.10.048","article-title":"New discoveries in the pathogenesis and classification of vitiligo","volume":"77","author":"Rodrigues","year":"2017","journal-title":"J Am Acad Dermatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1042\/cs20200218","article-title":"Homocysteine induces melanocytes apoptosis via PERK-eIF2\u03b1-CHOP pathway in vitiligo","volume":"134","author":"Chen","year":"2020","journal-title":"Clin Sci (Lond)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1152\/physrev.1950.30.1.91","article-title":"Biochemistry of melanin formation","volume":"30","author":"Lerner","year":"1950","journal-title":"Physiol Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1385\/CBB:41:3:415","article-title":"Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells","volume":"41","author":"Shi","year":"2004","journal-title":"Cell Biochem Biophys"},{"key":"B27","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1111\/j.1600-0625.2007.00675.x","article-title":"Regulation of melanogenesis\u2013controversies and new concepts","volume":"17","author":"Schallreuter","year":"2008","journal-title":"Exp Dermatol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.det.2007.04.010","article-title":"Advances in melanocyte basic science research","volume":"25","author":"Schallreuter","year":"2007","journal-title":"Dermatol Clin"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/php.12285","article-title":"Photooxidation of tetrahydrobiopterin under UV irradiation: Possible pathways and mechanisms","volume":"90","author":"Buglak","year":"2014","journal-title":"Photochem Photobiol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"19273","DOI":"10.1038\/s41598-020-76361-2","article-title":"Identifying environmental risk factors for inflammatory bowel diseases: A mendelian randomization study","volume":"10","author":"Carreras-Torres","year":"2020","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195171693.001.0001","volume-title":"Principles of nutritional assessment","author":"Gibson","year":"2005"},{"key":"B32","volume-title":"The megaloblastic anaemias","author":"Chanarin","year":"1969"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3109\/00365527109180702","article-title":"Absorption of cyanocobalamin, coenzyme b 12 , methylcobalamin, and hydroxocobalamin at different dose levels","volume":"6","author":"Adams","year":"1971","journal-title":"Scand J Gastroenterol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.clnesp.2017.10.004","article-title":"Surplus vitamin B(12) use does not reduce fatigue in patients with irritable bowel syndrome or inflammatory bowel disease: A randomized double-blind placebo-controlled trial","volume":"23","author":"Scholten","year":"2018","journal-title":"Clin Nutr ESPEN"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00076.2011","article-title":"B-vitamin deficiency is protective against DSS-induced colitis in mice","volume":"301","author":"Benight","year":"2011","journal-title":"Am J Physiol Gastrointest Liver Physiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1139799\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T17:27:12Z","timestamp":1702056432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1139799\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,10]]},"references-count":35,"alternative-id":["10.3389\/fimmu.2023.1139799"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1139799","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,10]]},"article-number":"1139799"}}