AccScience Publishing / EJMO / Online First / DOI: 10.36922/ejmo.7099
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ORIGINAL RESEARCH ARTICLE

Causal association between Vitamin D levels and head-and-neck cancer: A Mendelian randomization study

Xiaosong Ru1 ,  Ziying Su1 ,  Yong Guo2*
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1 The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
2 Department of Medical Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
EJMO, 7099 https://doi.org/10.36922/ejmo.7099
Submitted: 7 December 2024 | Revised: 23 January 2025 | Accepted: 18 February 2025 | Published: 15 April 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Observational studies have revealed inconsistent findings regarding the association between Vitamin D levels and head-and-neck cancer (HNC). Therefore, this study aimed to examine the possible causality of Vitamin D for HNC risk using two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Single-nucleotide polymorphisms closely associated with Vitamin D levels were selected from the genome-wide association research database as instrumental variables. The analytical approaches utilized included inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analysis was performed to verify the robustness of MR findings. In addition, the causation of Vitamin D on HNC risk was assessed by controlling for the influences of smoking and alcohol intake through MVMR analysis. IVW (odds ratio = 0.9958, 95% confidence interval = 0.9934 – 0.9983, p = 0.0007) indicated that Vitamin D levels were negatively related to HNC risk. The weighted median yielded the same result. The results of the MVMR analysis further supported the role of Vitamin D in mitigating HNC risk. The sensitivity analysis revealed the absence of heterogeneity or pleiotropy of the instrumental variables, proving our results reliable without significant bias. This study offers genetic evidence in favor of the causality of Vitamin D for HNC risk. Increasing Vitamin D intake may help lower HNC risk.

Keywords
Head-and-neck cancer
Vitamin D
Mendelian randomization
Causality
Funding
This research was supported by the National Natural Science Foundation of China (Grant No. 81973805); the Zhejiang Provincial Project for the key discipline of traditional Chinese Medicine (Yong Guo, no. 2017- XK-A09); and the Academic Inheritance and Specialty Construction of Famous and Elderly Chinese Medicine Practitioners in Zhejiang Province (2A11543).
Conflict of interest
The authors declare no conflicts of interest.
References
  1. Mody MD, Rocco JW, Yom SS, Haddad RI, Saba NF. Head and neck cancer. Lancet. 2021;398(10318):2289-2299. doi: 10.1016/S0140-6736(21)01550-6

 

  1. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6(1):92. doi: 10.1038/s41572-020-00224-3

 

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660

 

  1. Guo K, Xiao W, Chen X, Zhao Z, Lin Y, Chen G. Epidemiological trends of head and neck cancer: A population-based study. Biomed Res Int. 2021;2021:1738932. doi: 10.1155/2021/1738932

 

  1. Pu Y, Zhu G, Xu Y, et al. Association between vitamin D exposure and head and neck cancer: A systematic review with meta-analysis. Front Immunol. 2021;12:627226. doi: 10.3389/fimmu.2021.627226

 

  1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. doi: 10.1056/NEJMra070553

 

  1. Rebelos E, Tentolouris N, Jude E. The role of vitamin D in health and disease: A narrative review on the mechanisms linking vitamin D with disease and the effects of supplementation. Drugs. 2023;83(8):665-685. doi: 10.1007/s40265-023-01875-8

 

  1. Fleet JC, DeSmet M, Johnson R, Li Y. Vitamin D and cancer: A review of molecular mechanisms. Biochem J. 2012;441(1):61-76. doi: 10.1042/BJ20110744

 

  1. Starska-Kowarska K. Role of vitamin D in head and neck cancer-immune function, anti-tumour effect, and its impact on patient prognosis. Nutrients. 2023;15(11):2592. doi: 10.3390/nu15112592

 

  1. Arayici ME, Basbinar Y, Ellidokuz H. Vitamin D intake, serum 25-hydroxyvitamin-D (25(OH)D) levels, and cancer risk: A comprehensive meta-meta-analysis including meta-analyses of randomized controlled trials and observational epidemiological studies. Nutrients. 2023;15(12):2722. doi: 10.3390/nu15122722

 

  1. 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):1586-1591. doi: 10.1093/ajcn/85.6.1586

 

  1. Fanidi A, Muller DC, Midttun Ø, et al. Circulating vitamin D in relation to cancer incidence and survival of the head and neck and oesophagus in the EPIC cohort. Sci Rep. 2016;6:36017. doi: 10.1038/srep36017

 

  1. Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem. 2013;59(5):771-780. doi: 10.1373/clinchem.2012.201939

 

  1. Mäkitie A, Tuokkola I, Laurell G, et al. Vitamin D in head and neck cancer: A systematic review. Curr Oncol Rep. 2020;23(1):5. doi: 10.1007/s11912-020-00996-7

 

  1. Arem H, Weinstein SJ, Horst RL, et al. Serum 25-hydroxyvitamin D and risk of oropharynx and larynx cancers in Finnish men. Cancer Epidemiol Biomarkers Prev. 2011;20(6):1178-1184. doi: 10.1158/1055-9965.EPI-11-0153

 

  1. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA. 2017;318(19):1925-1926. doi: 10.1001/jama.2017.17219

 

  1. Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: Update for summer 2023. Wellcome Open Res. 2023;4:186. doi: 10.12688/wellcomeopenres.15555.3

 

  1. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601

 

  1. Dai Y, Chen Y, Pu Y, Jiang R. Circulating vitamin D concentration and risk of 14 cancers: A bidirectional Mendelian randomization study. J Cancer Res Clin Oncol. 2023;149(17):15457-15467. doi: 10.1007/s00432-023-05322-9

 

  1. Lin T, Zhou F, Mao H, Xie Z, Jin Y. Vitamin D and idiopathic pulmonary fibrosis: A two-sample Mendelian randomization study. BMC Pulm Med. 2023;23(1):309. doi: 10.1186/s12890-023-02589-z

 

  1. Zhang Z, Qiu S, Wang Z, Hu Y. Vitamin D levels and five cardiovascular diseases: A Mendelian randomization study. Heliyon. 2024;10(1):e23674. doi: 10.1016/j.heliyon.2023.e23674

 

  1. Sanderson E, Davey Smith G, Windmeijer F, Bowden J. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol. 2019;48(3):713-727. doi: 10.1093/ije/dyy262

 

  1. Jiang X, O’Reilly PF, Aschard H, et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun. 2018;9(1):260. doi: 10.1038/s41467-017-02662-2

 

  1. Howe LJ, Nivard MG, Morris TT, et al. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects. Nat Genet. 2022;54(5):581-592. doi: 10.1038/s41588-022-01062-7

 

  1. Bowden J, Del Greco MF, Minelli C, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: Moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728-742. doi: 10.1093/ije/dyy258

 

  1. Slob EAW, Burgess S. A comparison of robust Mendelian randomization methods using summary data. Genet Epidemiol. 2020;44(4):313-329. doi: 10.1002/gepi.22295

 

  1. 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):512-525. doi: 10.1093/ije/dyv080

 

  1. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693-698. doi: 10.1038/s41588-018-0099-7

 

  1. Burgess S, Bowden J, Fall T, Ingelsson E, Thompson SG. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology. 2017;28(1):30-42. doi: 10.1097/EDE.0000000000000559

 

  1. Orell-Kotikangas H, Schwab U, Österlund P, Saarilahti K, Mäkitie O, Mäkitie AA. High prevalence of vitamin D insufficiency in patients with head and neck cancer at diagnosis. Head Neck. 2012;34(10):1450-1455. doi: 10.1002/hed.21954

 

  1. Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: Potential for anticancer therapeutics. Nat Rev Cancer. 2007;7(9):684-700. doi: 10.1038/nrc2196

 

  1. 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):342-357. doi: 10.1038/nrc3691

 

  1. Satake K, Takagi E, Ishii A, et al. Anti-tumor effect of vitamin A and D on head and neck squamous cell carcinoma. Auris Nasus Larynx. 2003;30(4):403-412. doi: 10.1016/s0385-8146(03)00091-9

 

  1. Meier JD, Enepekides DJ, Poirier B, Bradley CA, Albala JS, Farwell DG. Treatment with 1-alpha, 25-dihydroxyvitamin D3 (vitamin D3) to inhibit carcinogenesis in the hamster buccal pouch model. Arch Otolaryngol Head Neck Surg. 2007;133(11):1149-1152. doi: 10.1001/archotol.133.11.1149

 

  1. Bochen F, Balensiefer B, Körner S, et al. Vitamin D deficiency in head and neck cancer patients-prevalence, prognostic value and impact on immune function. Oncoimmunology. 2018;7(9):e1476817. doi: 10.1080/2162402X.2018.1476817

 

  1. Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12(2):465-472. doi: 10.1158/1078-0432.CCR-05-1886

 

  1. Izreig S, Hajek M, Edwards HA, et al. The role of vitamin D in head and neck cancer. Laryngoscope Investig Otolaryngol. 2020;5(6):1079-1088. doi: 10.1002/lio2.469

 

  1. Nakamura K, Smyth MJ. Targeting cancer-related inflammation in the era of immunotherapy. Immunol Cell Biol. 2017;95(4):325-332. doi: 10.1038/icb.2016.126

 

  1. Jeon SM, Shin EA. Exploring vitamin D metabolism and function in cancer. Exp Mol Med. 2018;50(4):1-14. doi: 10.1038/s12276-018-0038-9

 

  1. Ma J, Ma Z, Li W, et al. The mechanism of calcitriol in cancer prevention and treatment. Curr Med Chem. 2013;20(33):4121-4130. doi: 10.2174/09298673113209990195
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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