The causal associations of 25(OH)D and its metabolites with oropharyngeal cancer risk: a Mendelian randomization study
DOI:
https://doi.org/10.2340/aos.v84.44053Keywords:
oropharyngeal cancer, mendelian randomization, 25(OH)D, 25(OH)D3, C3-epi-25(OH)D3Abstract
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.
Methods: 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–Egger) were also conducted. Leave-one-out and Cochran’s Q tests were concurrently used as sensitivity analyses to test and adjust for pleiotropy.
Results: 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 = 0.24–0.91, 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 = 0.28–0.91, 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.
Conclusions: 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.
The registration number is INPLASY202490081.
Downloads
References
Qadir MI, Rasul A, Akash MSH, Irfan M, Ibrahim MR, Hussain SB. Review: importance of vitamin D in cancer management. Pak J Pharm Sci. 2020;33(4):1711–8.
Revez JA, Lin T, Qiao Z, Xue A, Holtz Y, Zhu Z, et al. Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration. Nat Commun. 2020;11(1):1647. https://doi.org/10.1038/s41467-020-15421-7 DOI: https://doi.org/10.1038/s41467-020-15421-7
Zheng J-SID, Luan J, Sofianopoulou E, Sharp SJ, Day FR, Imamura F, et al. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: a metaanalysis and Mendelian randomization analysis. PLoS Med. 2020;17(10):e1003394. DOI: https://doi.org/10.1371/journal.pmed.1003394
Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G, et al. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nat Genet. 2016;48(12):1544–50. https://doi.org/10.1038/ng.3685 DOI: https://doi.org/10.1038/ng.3685
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;33:159–71. https://doi.org/10.1016/j.cct.2011.09.009 DOI: https://doi.org/10.1016/j.cct.2011.09.009
Yin L, Ordóñez-Mena JM, Chen T, Schöttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and metaanalysis. Prev Med. 2013;57:753–64. https://doi.org/10.1016/j.ypmed.2013.08.026 DOI: https://doi.org/10.1016/j.ypmed.2013.08.026
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33–44.
Ma Y, Trump DL, Johnson CS. Vitamin D in combination cancer treatment. J. Cance. 2010;1:101–7. https://doi.org/10.7150/jca.1.101 DOI: https://doi.org/10.7150/jca.1.101
Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4–5):309–16. https://doi.org/10.1016/j.oraloncology.2008.06.002 DOI: https://doi.org/10.1016/j.oraloncology.2008.06.002
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660 DOI: https://doi.org/10.3322/caac.21660
Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22. https://doi.org/10.1093/ije/dyg070 DOI: https://doi.org/10.1093/ije/dyg070
Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89–98. https://doi.org/10.1093/hmg/ddu328 DOI: https://doi.org/10.1093/hmg/ddu328
Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27(R2):R195–208. https://doi.org/10.1093/hmg/ddy163 DOI: https://doi.org/10.1093/hmg/ddy163
Lawlor DA, Borges MC, Palmer T, Hartwig FP. A Mendelian randomization dictionary: useful definitions and descriptions for undertaking, understanding and interpreting Mendelian Randomization studies [Interent]. [cited 2022 Jun 6]. Available from: https://osf.io/preprints/osf/6yzs7
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14. https://doi.org/10.1002/gepi.21965 DOI: https://doi.org/10.1002/gepi.21965
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):512–25. https://doi.org/10.1093/ije/dyv080 DOI: https://doi.org/10.1093/ije/dyv080
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: https://doi.org/10.3390/nu15020422
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. 2017:249:78–85. https://doi.org/10.1016/j.psychres.2016.12.052 DOI: https://doi.org/10.1016/j.psychres.2016.12.052
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: https://doi.org/10.1001/jamaoncol.2018.2178
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):342–57. https://doi.org/10.1038/nrc3691 DOI: https://doi.org/10.1038/nrc3691
Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. Br J Cancer. 2014;111(5):976–80. https://doi.org/10.1038/bjc.2014.294 DOI: https://doi.org/10.1038/bjc.2014.294
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):28–48. https://doi.org/10.1093/epirev/mxx005 DOI: https://doi.org/10.1093/epirev/mxx005
Bauer SR, Hankinson SE, Bertone Johnson ER, Ding EL. Plasma vitamin D levels, menopause, and risk of breast cancer: dose- response meta-analysis of prospective studies. Medicine (Baltimore). 2013;92(3):123–31. https://doi.org/10.1097/MD.0b013e3182943bc2 DOI: https://doi.org/10.1097/MD.0b013e3182943bc2
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: https://doi.org/10.3389/fonc.2023.1154107
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;149:13155–62. https://doi.org/10.1007/s00432-023-05140-z DOI: https://doi.org/10.1007/s00432-023-05140-z
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):4315–22. https://doi.org/10.1093/hmg/ddy307 DOI: https://doi.org/10.1093/hmg/ddy307
Ong JS, Cuellar-Partida G, Lu Y. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. Australian Ovarian Cancer Study. Int J Epidemiol. 2016;45(5):1619–30. DOI: https://doi.org/10.1093/ije/dyw207
Katagiri R, Goto A, Nakano S, Nakatochi M, Koyanagi YN, Iwagami M, et al. Association of 25-hydroxyvitamin D with risk of overall and colorectal cancer among Japanese using a Mendelian randomization approach. Sci Rep. 2023;13(1):2384. https://doi.org/10.1038/s41598-023-29596-8 DOI: https://doi.org/10.1038/s41598-023-29596-8
McCullough ML, Zoltick ES, Weinstein SJ, Fedirko V, Wang M, Cook NR, et al. Circulating vitamin D and colorectal cancer risk: an international pooling project of 17 cohorts. J Natl Cancer Inst. 2019;111(2):158–69. DOI: https://doi.org/10.1093/jnci/djy087
Kim Y, Chang Y, Cho Y, Chang J, Kim K, Park D-I, et al. Serum 25-hydroxyvitamin D levels and risk of colorectal cancer: an age-stratified analysis. Gastroenterology. 2023;165(4):920–31. https://doi.org/10.1053/j.gastro.2023.06.029 DOI: https://doi.org/10.1053/j.gastro.2023.06.029
Manson JE, Cook, Lee I-M, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33–44. https://doi.org/10.1056/NEJMoa1809944 DOI: https://doi.org/10.1056/NEJMoa1809944
Chandler PD, Chen WY, Ajala ON, Hazra A, Cook N, Bubes V, et al. Effect of vitamin D3 supplements on development of advanced cancer: a secondary analysis of the VITAL randomized clinical trial. VITAL Research Group. JAMA Netw Open. 2020;3(11):e2025850. https://doi.org/10.1001/jamanetworkopen.2020.25850 DOI: https://doi.org/10.1001/jamanetworkopen.2020.25850
Muñoz A, Grant WB. Vitamin D and cancer: an historical overview of the epidemiology and mechanisms. Nutrients. 2022;14(7):1448. https://doi.org/10.3390/nu14071448 DOI: https://doi.org/10.3390/nu14071448
Pilz S, Trummer C, Theiler-Schwetz V, Grübler MR, Verheyen ND, Odler B, et al. Critical appraisal of large vitamin D randomized controlled trials. Nutrients. 2022;14(2):303. https://doi.org/10.3390/nu14020303 DOI: https://doi.org/10.3390/nu14020303
Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48–54. https://doi.org/10.1111/nure.12090 DOI: https://doi.org/10.1111/nure.12090
Carlberg C, Muñoz A. An update on vitamin D signaling and cancer. Semin Cancer Biol. 2022;79:217–30. https://doi.org/10.1016/j.semcancer.2020.05.018 DOI: https://doi.org/10.1016/j.semcancer.2020.05.018
Giampazolias E, da Costa MP, Lam KC, Lim KHJ, Cardoso A, Piot C, et al. Vitamin D regulates microbiome-dependent cancer immunity. Science. 2024;384(6694):428–37. https://doi.org/10.1126/science.adh7954 DOI: https://doi.org/10.1126/science.adh7954
Lappe J, Watson P, Travers-Gustafson D, Recker R, Garland C, Gorham E, et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA. 2017;317(12):1234–43. https://doi.org/10.1001/jama.2017.2115 DOI: https://doi.org/10.1001/jama.2017.2115
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85(6):1586–91. https://doi.org/10.1093/ajcn/85.6.1586 DOI: https://doi.org/10.1093/ajcn/85.6.1586
Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002. BMC Cancer. 2006;6:264. https://doi.org/10.1186/1471-2407-6-264 DOI: https://doi.org/10.1186/1471-2407-6-264
Wilson Westmark NL, Sroussi H, Tamayo I, Villa A. Vitamin D status in patients with oropharyngeal cancer: association with HPV status and prognosis. Oral Dis. 2023;29(2):542–546. https://doi.org/10.1111/odi.13965 DOI: https://doi.org/10.1111/odi.13965
Avila E, Noriega-Mejía BJ, González-Macías J, Cortes-Hernández U, García-Quiroz J, García-Becerra R, et al. The preventive role of the vitamin D endocrine system in cervical cancer. Int J Mol Sci. 2023;24(10):8665. https://doi.org/10.3390/ijms24108665 DOI: https://doi.org/10.3390/ijms24108665
Giammanco M, Majo DD, Guardia ML, Aiello S, Crescimannno M, Flandina C, et al. Vitamin D in cancer chemoprevention. Pharm Biol. 2015;53:1399–1434. https://doi.org/10.3109/13880209.2014.988274 DOI: https://doi.org/10.3109/13880209.2014.988274
Additional Files
Published
Issue
Section
License
Copyright (c) 2025 YaoHui Yu, Yu Zhou
This work is licensed under a Creative Commons Attribution 4.0 International License.
Acta Odontologica Scandinavica publishes original research papers as well as critical reviews relevant to the diagnosis, epidemiology, health service, prevention, aetiology, pathogenesis, pathology, physiology, microbiology, development and treatment of diseases affecting tissues of the oral cavity and associated structures including papers on cause and effect or explanatory/associative relationships for experimental or observational studies.
