{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:26:41Z","timestamp":1789140401242,"version":"build-2803163510"},"reference-count":80,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Health","doi-asserted-by":"publisher","award":["R01DK082766"],"award-info":[{"award-number":["R01DK082766"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Health","doi-asserted-by":"publisher","award":["NOT-HG-11-009"],"award-info":[{"award-number":["NOT-HG-11-009"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Health","doi-asserted-by":"publisher","award":["R01DK118427"],"award-info":[{"award-number":["R01DK118427"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases-NIDDK","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute-NHGRI","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Dr. Geoffrey Altshuler Children\u2019s Hospital Foundation Endowment"},{"DOI":"10.13039\/100001298","name":"Presbyterian Health Foundation of Oklahoma","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001298","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01nbasn20","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Vitamin D (25(OH)D) deficiency affects over one billion people globally and is associated with type 2 diabetes (T2D) and cardiometabolic diseases. However, causal relationships remain unclear, as vitamin D supplementation has shown limited benefit in reducing the risk of T2D. Genetic studies have identified variants that influence circulating 25(OH)D levels, but whether genetically determined vitamin D status predicts cardiometabolic outcomes remains uncertain. Methods and Results: Using multi-ethnic populations from the UK Biobank (471,861) and the Asian Indian Diabetic Heart Study (3486), we performed genome-wide univariate and polygenic risk score (PRS)-based bidirectional MR analyses to determine the causal association between vitamin D and T2D. A polygenic score of vitamin D\u2013raising alleles did not affect the risk of T2D or cardiovascular disease. In contrast, a higher T2D PRS was strongly associated with an increased risk for 25(OH)D deficiency. Genetically instrumented per SD increase in T2D PRS was predicted to significantly (p = 9.5 \u00d7 10\u221231) reduce circulating 25(OH)D (\u03b2 = \u22129.1 nmol\/L; 95% CI: \u22128.9 to \u22129.3). The ancestry-specific univariate MR and sensitivity analyses confirmed that vitamin D levels reduced significantly with increasing T2D risk across all ancestries. Conclusions: Our findings suggest low circulating vitamin D levels are unlikely to causally predict T2D risk but may serve as a marker for secondary prevention in endocrine and cardiovascular health. Instead, genetic susceptibility to T2D appears to contribute to vitamin D insufficiency, which may lead to cardiovascular complications. Further studies are needed to clarify the mechanisms underlying vitamin D deficiency in diabetes.<\/jats:p>","DOI":"10.3390\/nu18121944","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:58:38Z","timestamp":1781661518000},"page":"1944","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Type 2 Diabetes Causally Reduces Circulating Vitamin D Levels: A Multi-Ancestry Mendelian Randomization Study"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1632-8201","authenticated-orcid":false,"given":"Madhusmita","family":"Rout","sequence":"first","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2320-1134","authenticated-orcid":false,"given":"Piers","family":"Blackett","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Fellow of the American Academy of Pediatrics (FAAP), Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, Oklahoma City, OK 73104, USA"},{"name":"Fellow of the National Lipid Association (FNLA), Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7203-8655","authenticated-orcid":false,"given":"Dharambir K.","family":"Sanghera","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Fellow of the American Heart Association (FAHA), Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., Rm 317 BMSB, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1080S","DOI":"10.1093\/ajcn\/87.4.1080S","article-title":"Vitamin D deficiency: A worldwide problem with health consequences","volume":"87","author":"Holick","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1038\/s41430-020-0558-y","article-title":"Vitamin D deficiency 2.0: An update on the current status worldwide","volume":"74","author":"Amrein","year":"2020","journal-title":"Eur. J. Clin. 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