{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:51:44Z","timestamp":1784742704102,"version":"3.55.0"},"reference-count":43,"publisher":"MJS Publishing, Medical Journals Sweden AB","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["AOS"],"abstract":"<jats:p>Background: Previous studies have suggested that there are distinct correlations of 25-hydroxyvitamin D (25(OH)D) and its metabolites with the risk of developing health conditions and cancer; however, the precise nature of these associations in patients with oropharyngeal cancer (OPC) is unknown. Our primary objective was to evaluate the causal impact of 25(OH)D and its metabolites, including 25(OH)D3 and its epimer C3-epi-25(OH)D3, on susceptibility to OPC through the use of Mendelian randomization (MR) methodology.\nMethods: Mendelian randomization analysis was performed on data from 291 patients with OPC from Europe, North America, and South America using genetic variant strongly related to C3-epi-25(OH)D3, 25(OH)D, and 25(OH)D3 exposure. The primary analytical method for two-sample MR analysis was inverse-variance weighting (IVW); supplemental analyses (weighted median [WM], MR\u2013Egger) were also conducted. Leave-one-out and Cochran\u2019s Q tests were concurrently used as sensitivity analyses to test and adjust for pleiotropy.\nResults: Our MR analysis provided evidence suggesting that greater 25(OH)D3 levels are causally associated with a decreased risk of developing OPC within the European population (WM OR = 0.47, 95% CI = 0.24\u20130.91, p = 0.03). Only one of the 21 MR analyses yielded significant results; for this MR analysis, the IVW results were significant, but subsequent leave-one-out analyses revealed instability in the causal association. However, the association was significant when rs9304669 was excluded (OR = 0.51, 95% CI = 0.28\u20130.91, p = 0.02), whereas the other results were not statistically significant. The sensitivity analysis indicated that the results were reliable, with no observed heterogeneity or pleiotropy.\nConclusions: There was no evidence that 25(OH)D, 25(OH)D3 or C3-epi-25(OH)D3 levels are associated with OPC risk or that 25OHD supplementation in the general population prevents OPC.\nThe registration number is INPLASY202490081.<\/jats:p>","DOI":"10.2340\/aos.v84.44053","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T07:20:48Z","timestamp":1752736848000},"page":"398-407","source":"Crossref","is-referenced-by-count":1,"title":["The causal associations of 25(OH)D and its metabolites with oropharyngeal cancer risk: a Mendelian randomization study"],"prefix":"10.2340","volume":"84","author":[{"given":"YaoHui","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1183","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"117538","unstructured":"Qadir MI, Rasul A, Akash MSH, Irfan M, Ibrahim MR, Hussain SB. 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Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet. 2016;\u200b48(12):1544\u201350. https:\/\/doi.org\/10.1038\/ng.3685","DOI":"10.1038\/ng.3685"},{"key":"117542","doi-asserted-by":"crossref","unstructured":"Manson JE, Bassuk SS, Lee I-M, Cook NR, Albert MA, Gordon D, et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials. 2012;33:159\u201371. https:\/\/doi.org\/10.1016\/j.cct.2011.09.009","DOI":"10.1016\/j.cct.2011.09.009"},{"key":"117543","doi-asserted-by":"crossref","unstructured":"Yin L, Ord\u00f3\u00f1ez-Mena JM, Chen T, Sch\u00f6ttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and metaanalysis. 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Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304\u201314. https:\/\/doi.org\/10.1002\/gepi.21965","DOI":"10.1002\/gepi.21965"},{"key":"117553","doi-asserted-by":"crossref","unstructured":"Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression. Int J Epidemiol. 2015;44(2):512\u201325. https:\/\/doi.org\/10.1093\/ije\/dyv080","DOI":"10.1093\/ije\/dyv080"},{"key":"117554","doi-asserted-by":"crossref","unstructured":"Lawler T, Andersen SW. Serum 25-hydroxyvitamin D and cancer risk: a systematic review of Mendelian randomization studies. Nutrients. 2023;15(2):422. https:\/\/doi.org\/10.3390\/nu15020422","DOI":"10.3390\/nu15020422"},{"key":"117555","doi-asserted-by":"crossref","unstructured":"Adamson J, Lally J, Gaughran F, Krivoy A, Allen L, Stubbs B. Correlates of vitamin D in psychotic disorders: a comprehensive systematic review. Psychiatry Res. 2017:249:78\u201385. https:\/\/doi.org\/10.1016\/\u200bj.psychres.2016.12.052","DOI":"10.1016\/j.psychres.2016.12.052"},{"key":"117556","doi-asserted-by":"crossref","unstructured":"Scragg R, Khaw K-T, Toop L, et al. Monthly high-dose vitamin D supplementation and cancer risk: a post hoc analysis of the Vitamin D Assessment randomized clinical trial. JAMA Oncol. 2018;4(11):e182178. https:\/\/doi.org\/10.1001\/jamaoncol.2018.2178","DOI":"10.1001\/jamaoncol.2018.2178"},{"key":"117557","doi-asserted-by":"crossref","unstructured":"Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14(5):342\u201357. https:\/\/doi.org\/10.1038\/nrc3691","DOI":"10.1038\/nrc3691"},{"key":"117558","doi-asserted-by":"crossref","unstructured":"Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer. 2014;111(5):\u200b976\u201380. https:\/\/doi.org\/10.1038\/bjc.2014.294","DOI":"10.1038\/bjc.2014.294"},{"key":"117559","doi-asserted-by":"crossref","unstructured":"Mondul AM, Weinstein SJ, Layne TM, Albanes D. Vitamin D and cancer risk and mortality: state of the science, gaps, and challenges. Epidemiol Rev. 2017;39(1):28\u201348. https:\/\/doi.org\/10.1093\/epirev\/mxx005","DOI":"10.1093\/epirev\/mxx005"},{"key":"117560","doi-asserted-by":"crossref","unstructured":"Bauer SR, Hankinson SE, Bertone Johnson ER, Ding EL. Plasma vitamin D levels, menopause, and risk of breast cancer: dose-\u00ad response meta-analysis of prospective studies. Medicine (Baltimore). 2013;92(3):123\u201331. https:\/\/doi.org\/10.1097\/MD.0b013e3\u200b182943bc2","DOI":"10.1097\/MD.0b013e3182943bc2"},{"key":"117561","doi-asserted-by":"crossref","unstructured":"Cai B, Lin Q, Ke R, Shan X, Yu J, Ni X, et al. Causal association between serum 25-Hydroxyvitamin D levels and cutaneous melanoma: a two-sample Mendelian randomization study. Front Oncol. 2023;13:1154107. https:\/\/doi.org\/10.3389\/fonc.2023.1154107","DOI":"10.3389\/fonc.2023.1154107"},{"key":"117562","doi-asserted-by":"crossref","unstructured":"Chen B, Diallo MT, Ma Y, Wang D. The association of vitamin D and digestive system cancers: a comprehensive Mendelian randomization study. J Cancer Res Clin Oncol. 2023;149:13155\u201362. https:\/\/doi.org\/10.1007\/s00432-023-05140-z","DOI":"10.1007\/s00432-023-05140-z"},{"key":"117563","doi-asserted-by":"crossref","unstructured":"Ong JS, Gharahkhani P, An J, Law MH, Whiteman DC, Neale RE, et al. Vitamin D and overall cancer risk and cancer mortality: a Mendelian randomization study. Hum Mol Genet. 2018;27(24):4315\u201322. https:\/\/doi.org\/10.1093\/hmg\/ddy307","DOI":"10.1093\/hmg\/ddy307"},{"key":"117564","doi-asserted-by":"crossref","unstructured":"Ong JS, Cuellar-Partida G, Lu Y. 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