Vitamin D Receptor in Human Health and Disease: An Overview

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Authors

  • Jyoti Kashyap
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi - 110067 ,IN
  • Ayushi Chhabra
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi - 110067 ,IN
  • Sheeba Rizvi
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi - 110067 ,IN
  • Rakesh K. Tyagi
     Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi - 110067 ,IN

DOI:

https://doi.org/10.18311/jer/2022/28911

Keywords:

Nuclear Receptors, Polymorphism, Retinoid X Receptor, Transcription Factors, Vitamin D Receptor
Vitamin D receptor polymorphism

Abstract

Vitamin D Receptor (VDR) is a key regulator of bone metabolism and calcium homeostasis. Various investigations suggest its association with many life-threatening diseases including bone-related disorders, cancers, diabetes, cardiovascular diseases, infectious diseases and metabolic disorders. VDR forms a heterodimeric complex with Retinoid X Receptor (RXR) when activated with 1?,25-dihydroxyvitamin D3 and binds to vitamin D response elements (VDREs) in the DNA sequences located upstream of target genes. Ligand binding and heterodimerization play critical roles in receptor activation and gene regulation. Many studies have shown that any change in VDR function influences target gene functions. Numerous VDR polymorphisms have been reported in various populations around the world. Additionally, a number of case-control studies have established a link between the VDR polymorphism(s) and human diseases. However, some contradictory studies have also been reported. Recent investigations have identified several critical VDR polymorphism(s) that may influence or alter the receptor’s function and contribute to the genesis/etiology of disease states. In this review, we have highlighted and analyzed the relevance of VDR and its polymorphism(s) vis-a-vis risk to some disease conditions. The current review highlights the importance of VDR-SNPs in decoding the importance of a receptor as a transcription factor as well as a molecular marker for diagnosis of diverse health conditions.

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Published

2022-04-30

How to Cite

Kashyap, J., Chhabra, A., Rizvi, S., & Tyagi, R. K. (2022). Vitamin D Receptor in Human Health and Disease: An Overview. Journal of Endocrinology and Reproduction, 26(1), 01–23. https://doi.org/10.18311/jer/2022/28911

Issue

Volume 26, Issue 1, March 2022

Section

Review Article
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References

Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: Opening the X-files. Science. 2001; 294(5548):1866-70. https://doi.org/10.1126/science.294.5548.1866. PMid:11729302.

Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor? Arch Biochem Biophys. 2012; 523(1):123-33. https://doi.org/10.1016/j. abb.2012.04.001. PMid:22503810.

Uitterlinden AG, Fang Y, van Meurs JBJ, et al., Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states. J Steroid Biochem Mol Biol. 2004; 89-90:187-93. https://doi.org/10.1016/j.jsbmb.2004.03.083. PMid:15225770.

Baker AR, McDonell DP, Hughes M, et al., Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U.S.A. 1998; 85:3294-8. https://doi.org/10.1073/pnas.85.10.3294. PMid:2835767 PMCid:PMC280195.

Issa LL, Leong GM,. Eisman JA. Molecular mechanism of vitamin D receptor action. Inflamm Res. 1998; 47:451-475. https://doi. org/10.1007/s000110050360. PMid:9892040.

Black BE, Holaska JM, Rastinejad F, Paschal BM. DNA binding domains in diverse nuclear receptors function as nuclear export signals. Curr Biol. 2001; 11:1749-58. https://doi.org/10.1016/S0960-9822(01)00537-1.

Prüfer K, Barsony J. Retinoid X Receptor Dominates the Nuclear Import and Export of the Unliganded Vitamin D Receptor. Mol Endocrinol. 2002; 16:1738-51. https://doi.org/10.1210/me.2001-0345. PMid:12145331.

Pike JW. The Vitamin D Receptor: Discovery, Structure, and Function. Adv Organ Biol. 1998; 5:213-41. https://doi.org/10.1016/ S1569-2590(08)60114-7.

Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014; 21:319-29. https://doi. org/10.1016/j.chembiol.2013.12.016. PMid:24529992 PMCid:PMC3968073.

Hourai S, Rodrigues LC, Antony P, et al., Structure-Based Design of a Superagonist Ligand for the Vitamin D Nuclear Receptor. Chem Biol. 2008; 15:383-92. https://doi.org/10.1016/j.chembiol.2008.03.016. PMid:18420145.

Antony P, Sigueiro R, Huet T, et al., Structure-function relationships and crystal structures of the vitamin D receptor bound 2β-methyl-(20S,23S) and 2β-methyl-(20S,23R)-epoxymethano-1?,25-dihydroxyvitamin D3. J Med Chem. 2010; 53:1159-71. https://doi.org/10.1021/jm9014636. PMid:20070104.

EelenG, Valle N, Sato Y, et al., Superagonistic Fluorinated Vitamin D3 Analogs Stabilize Helix 12 of the Vitamin D Receptor. Chem Biol. 2008; 15:1029-34. https://doi.org/10.1016/j.chembiol.2008.08.008. PMid:18940664.

Eelen G, Verlinden L, Bouillon R, et al., CD-ring modified vitamin D3 analogs and their superagonistic action. J Steroid Biochem Mol Biol. 2010; 121:417-19. https://doi.org/10.1016/j.jsbmb.2010.01.010. PMid:20132886.

Tavera-Mendoza L, Wang TT, Lallemant B, et al., Convergence of vitamin D and retinoic acid signalling at a common hormone response element. EMBO Rep. 2006; 7:180-85. https://doi.org/10.1038/sj.embor.7400594. PMid:16322758 PMCid:PMC1369248.

Malloy PJ, Feldman D. Vitamin D resistance. Am J Med. 1999; 106:355-70. https://doi.org/10.1016/S0002-9343(98)00419-7.

Kittaka A, Saito N, Honzawa S, et al., Creative synthesis of novel vitamin D analogs for health and disease. J Steroid Biochem Mol Biol. 2007; 103:269-76. https://doi.org/10.1016/j.jsbmb.2006.12.002. PMid:17223554.

Dixon KM, Deo SS, Wong G, et al., Skin cancer prevention: a possible role of 1,25-dihydroxyvitamin D3 and its analogs. J Steroid Biochem Mol Biol. 2005; 97:137-43. https://doi.org/10.1016/j.jsbmb.2005.06.006. PMid:16039116.

Peleg S, Peterson KS, Suh BC, et al., Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1 alpha, 25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation. J Med Chem. 2006; 49:7513- 17. https://doi.org/10.1021/jm0609925. PMid:17149880.

De Clercq PJ, Buysser FD, Minne G, et al., The development of CD-ring modified analogs of 1 alpha,25- dihydroxyvitamin D. J Steroid Biochem Mol Biol. 2007; 103:206-12. https://doi.org/10.1016/j.jsbmb.2006.12.023. PMid:17218098.

Carlberg C, Molnar F, Mourino A. Vitamin D receptor ligands: the impact of crystal structures. Expert Opin Ther Pat. 2012; 22:417-35. https://doi.org/10.1517/13543776.2012.673590. PMid:22449247.

Sokolowska K, Mouriño A, Sicinski RR, et al., Synthesis and biological evaluation of 6-methyl analog of 1 alpha,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 2010; 121:29-33. https://doi.org/10.1016/j.jsbmb.2010.02.008. PMid:20153829.

Sawada D, Tsukuda Y, Saito H, et al., Development of 14-epi-19-nortachysterol and its unprecedented binding configuration for the human vitamin D receptor. J Am Chem Soc. 2011; 133:7215-21. https://doi.org/10.1021/ja201481j. PMid:21500802.

Carlberg C, Molnar F. Detailed molecular understanding of agonistic and antagonistic vitamin D receptor ligands. Curr Top Med Chem. 2006; 6:1243-53. https://doi.org/10.2174/156802606777864908. PMid:16848738.

Zhao XY, Eccleshall TR, Krishnan AV, et al., Analysis of vitamin D analog-induced heterodimerization of vitamin D receptor with retinoid X receptor using the yeast two-hybrid system. Mol Endocrinol. 2014; 11:366-78. https://doi.org/10.1210/mend.11.3.9895. PMid:9058382.

Hsieh JC, Jurutka PW, Selznick SH, et al., The T-box near the zinc fingers of the human vitamin D receptor is required for heterodimeric DNA binding and transactivation. Biochem Biophys Res Commun. 1995; 215:1-7. https://doi.org/10.1006/ bbrc.1995.2426. PMid:7575575.

Whitfield GK, Hseih JC, Nakajima S, et al., A highly conserved region in the hormone-binding domain of the human vitamin D receptor contains residues vital for heterodimerization with retinoid X receptor and for transcriptional activation. Mol Endocrinol. 2014; 9:1166-79. https://doi.org/10.1210/mend.9.9.7491109.

Clemens TL, Garrett KP, Zhou XY, et al., Immunocytochemical localization of the 1,25-dihydroxyvitamin d3 receptor in target cells. Endocrinology. 1988; 122:1224-30. https://doi.org/10.1210/endo-122-4-1224. PMid:2831024.

Hunziker W, Walters MR, Bishop JE, Norman AW. Unoccupied and in vitro and in vivo occupied 1,25-dihydroxyvitamin D3 intestinal receptors. Multiple biochemical forms and evidence for transformation. J Biol Chem. 1983; 258:8642-48. https://doi. org/10.1016/S0021-9258(18)32105-7.

Berger U, Wilson P, McClelland RA, et al., Immunocytochemical detection of 1,25-dihydroxyvitamin D receptors in normal human tissues. J Clin Endocrinol Metab. 1988; 67:607-13 . https://doi.org/10.1210/jcem-67-3-607. PMid:2842365.

Luo Z, Rouvinen J, Mäenpää PH. A peptide C-terminal to the second Zn finger of human vitamin D receptor is able to specify nuclear localization. Eur J Biochem. 1994; 223:381-87. https://doi.org/10.1111/j.1432-1033.1994.tb19004.x. PMid:8055906.

Hsieh JC, Shimizu Y, Minoshima S, et al., Novel nuclear localization signal between the two DNA-binding zinc fingers in the human vitamin D receptor. J Cell Biochem. 1998; 70:94-109. https://doi.org/10.1002/(SICI)1097-4644(19980701)70:1<94::AIDJCB10> 3.0.CO;2-B.

Michigami T, Suga A, Yamazaki M, et al., Identification of amino acid sequence in the hinge region of human vitamin D receptor that transfers a cytosolic protein to the nucleus. J Biol Chem. 1999; 274:33531-38. https://doi.org/10.1074/jbc.274.47.33531. PMid:10559238.

Yasmin R, Williams RM, Xu M, Noy N. Nuclear import of the retinoid X receptor, the vitamin D receptor, and their mutual heterodimer. J Biol Chem. 2005; 280:40152-60. https://doi.org/10.1074/jbc.M507708200. PMid:16204233.

Dash AK, Yende AS, Tyagi RK. Novel application of red fluorescent protein (dsred-express) for the study of functional dynamics of nuclear receptors. J Fluoresc. 2017; 27:1225-31. https://doi.org/10.1007/s10895-017-2109-z. PMid:28470379.

Kumar S, Kashyap J, Thakur K, Tyagi RK. A Simple method for visual assessment and quantification of altered subcellular localization of nuclear receptors. Nuclear Receptors. 2021. p. 23-36. https://doi.org/10.1007/978-3-030-78315-0_2.

Civitelli R, Ziambaras K. Calcium and phosphate homeostasis: concerted interplay of new regulators. J Endocrinol Invest. 2011; 34:3-7.

Saito H, Maeda A, Ohtomo S, et al., Circulating FGF-23 is regulated by 1 alpha, 25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem. 2005; 280:2543-49. https://doi.org/10.1074/jbc.M408903200. PMid:15531762.

Meyer MB, Watanuki M, Kim S, et al., The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin d receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in Intestinal cells. Mol Endocrinol. 2006; 20:1447-61. https://doi.org/10.1210/me.2006-0031. PMid:16574738.

Kim S, Yamazaki M, Zella LA, et al., Activation of receptor activator of nf- b ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. Mol Cell Biol. 2006; 26(17):6469-86. https://doi.org/10.1128/MCB.00353-06. PMid:16914732 PMCid:PMC1592822.

Wang QM, Jones JB, Studzinski GP. Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1,25-dihydroxyvitamin D3 in HL60 cells. Cancer Res. 1996; 56:264-67.

Verlinden L, Verstuyf A, Convents R, et al., Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells. Mol Cell Endocrinol. 1998; 142:57-65. https://doi.org/10.1016/S0303-7207(98)00117-8.

Peng L, Malloy PJ, Feldman D. Identification of a Functional vitamin D response element in the human insulin-like growth factor binding protein-3 promoter. Mol Endocrinol. 2004; 18:1109-19. https://doi.org/10.1210/me.2003-0344. PMid:14963110.

Gil Á, Plaza-Diaz J, Mesa MD. Vitamin D: Classic and novel actions. Ann Nutr Metab. 2018; 72:87-95. https://doi. org/10.1159/000486536. PMid:29346788.

Jones G, Strugnell SA, Deluca HF. Current understanding of the molecular actions of vitamin D physiol rev. 1998; 78:1193-231. https://doi.org/10.1152/physrev.1998.78.4. 1193.PMid:9790574.

Pike J.W, Meyer MB, Lee SM, et al., The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J Clin Invest. 2017; 127:1146-54. https://doi.org/10.1172/JCI88887. PMid:28240603 PMCid:PMC5373853.

Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005; 26:662-87. https://doi. org/10.1210/er.2004-0002. PMid:15798098.

Carlberg C, Seuter S, Heikkinen S. The first genome-wide view of vitamin D receptor locations and their mechanistic implications. Anticancer Res. 2012; 282:271-82.

Ryan JW, Anderson PH, Morris HA. Pleiotropic activities of vitamin D receptors- Adequate activation for multiple health outcomes. Clin Biochem Rev. 2015; 36:53-61.

Jeon S. Exploring vitamin D metabolism and function in cancer. Exp Mol Med. 2018; 50(4):1-14. https://doi.org/10.1038/s12276- 018-0038-9. PMCid:PMC5938036.

Gross C, Eccleshall TR, Malloy PJ, et al., The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal mexican-American women. J Bone Miner Res. 1996; 11:1850-55. https://doi.org/10.1002/jbmr.5650111204. PMid:8970885.

Taylor JA, Hirvonen A, Watson M, et al., Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res. 1996; 56:4108-10.

Li L, Wu B, Liu J, Yang L. Vitamin D receptor gene polymorphisms and type 2 diabetes : Arch Med Res. 2013; 44:235-41. https:// doi.org/10.1016/j.arcmed.2013.02.002. PMid:23506721.

Huang L, Liu C, Liao G, et al., Vitamin D receptor gene foki polymorphism contributes to increasing the risk of tuberculosis: An update meta-Analysis. Medicine (Baltimore). 2015;94:1-8. https://doi.org/10.1097/MD.0000000000002256. PMid:26705207 PMCid:PMC 4697973.

Laplana M, Royo JL, Fibla J. Vitamin D receptor polymorphisms and risk of enveloped virus infection: A meta-analysis. Gene. 2018; 678:384-94. https://doi.org/10.1016/j.gene.2018.08.017. PMid:30092343.

Saijo T, Ito M, Takeda E, Huq AHMM, et al., A unique mutation in the vitamin D receptor gene in three Japanese patients with vitamin D-dependent rickets type II: Utility of single-strand conformation polymorphism analysis for heterozygous carrier detection. Am J Hum Genet. 1991; 49: 668-73.

Arai H, Miyamoto K, Taketani Y, et al., A vitamin D receptor gene polymorphism in the translation initiation codon: Effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res. 1997; 12:915-21. https://doi. org/10.1359/jbmr.1997.12.6.915. PMid:9169350.

Gross C, Krishnan AV, Malloy PJ, et al., The vitamin D receptor gene start codon polymorphism: A functional analysis of FokI variants. J Bone Miner Res. 1998; 13:1691-99. https://doi.org/10.1359/jbmr.1998.13.11.1691. PMid:9797477.

Yamamoto H, Miyamoto K, Li B, et al., The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine. J Bone Miner Res. 1999; 14:240-247. https://doi.org/10.1359/jbmr.1999.14.2.240. PMid:9933478.

Arai H, Miyamoto KI, Yoshida M, et al., The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res. 2001; 16:1256-64. https://doi.org/10.1359/jbmr.2001.16.7.1256. PMid:11450701.

Morrison NA, Yeoman R, Kelly PJ, Eisman JA. Contribution of transacting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin. Proc Natl Acad Sci. 1992; 89:6665-69. https://doi.org/10.1073/ pnas.89.15.6665. PMid:1353882 PMCid:PMC49563.

Faraco JH, Morrison NA, Baker A, et al., ApaI dimorphism at the human vitamin D receptor gene locus. Nucleic Acids Res. 1989; 17:2150. https://doi.org/10.1093/nar/17.5.2150. PMid:2564666 PMCid:PMC317576.

Farrow S. Allelic variation and the vitamin D receptor. Lancet. 1994; 343:1242. https://doi.org/10.1016/S0140-6736(94)92147-4.

Fang Y, Van Meurs JB, D’Alesio, A, et al., Promoter and 3β-untranslated-region haplotypes in the vitamin d receptor gene predispose to osteoporotic fracture: The rotterdam study. Am J Hum Genet. 2005; 77:807-23. https://doi.org/10.1086/497438. PMid:16252240 PMCid:PMC1271389.

Halsall JA, Osborne JE, Potter L, et al., A novel polymorphism in the IA promoter region of the vitamin D receptor is associated with altered susceptibilty and prognosis in malignant melanoma. Br J Cancer. 2004; 91:765-70. https://doi.org/10.1038/sj.bjc.6602006. PMid:15238985 PMCid:PMC2364794.

Ye WZ, Reis AF, Velho G. Identification of a novel Tru9 I polymorphism in the human vitamin D receptor gene. J Hum Genet. 2000; 45:56-57. https://doi.org/10.1007/s100380050011. PMid:10697965.

John EM, Schwartz GG, Koo J, et al., Sun exposure, vitamin D receptor gene polymorphisms, and breast cancer risk in a multiethnic population. Am J Epidemiol. 2007; 166:1409-19. https://doi.org/10.1093/aje/kwm259. PMid:17934201.

Morrison NA, Qi JC, Tokita A, et al., Prediction of bone density from vitamin D receptor alleles. Nature. 1994; 367:284-87. https:// doi.org/10.1038/367284a0. PMid:8161378.

Uitterlinden AG, Pols HA, Burger H, et al., A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res. 1996; 11:1241-48. https://doi.org/10.1002/jbmr.5650110908. PMid:8864898.

Tokitan A, Matsumoto H, Morrison NA, et al., Vitamin D receptor alleles, bone mineral density and turnover in premenopausal Japanese women. J Bone Miner Res. 1996; 11:1003-09. https://doi.org/10.1002/jbmr.5650110718. PMid:8797122.

McClure L, Eccleshall TR, Gross C, et al., Vitamin D receptor polymorphisms, bone mineral density, and bone metabolism in postmenopausal Mexican-American women. J Bone Miner Res.1997; 12:234-40. https://doi.org/10.1359/jbmr.1997.12.2.234. PMid:9041055.

Tsai KS, Hsu SH, Cheng WC, et al., Bone mineral density and bone markers in relation to vitamin D receptor gene polymorphisms in Chinese men and women. Bone. 1996; 19:513-18. https://doi.org/10.1016/S8756-3282(96)00228-1.

Lundin AC, Soderkvist P, Eriksson B, et al., Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Cancer Res. 1999; 59:2332-34.

Cicek MS, Liu X, Schumacher FR, et al., Vitamin D receptor genotypes/haplotypes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2006; 15:2549-52. https://doi.org/10.1158/1055-9965.EPI-06-0409. PMid:17164384.

Correa-Cerro L, Berthon P, Haussler J, et al., Vitamin D receptor polymorphisms as markers in prostate cancer. Hum Genet. 1999; 105:281-87. https://doi.org/10.1007/s004399900119. PMid:10987658.

Cheteri MB, Stanford JL, Friedrichsen DM, et al., Vitamin D receptor gene polymorphisms and prostate cancer risk. Prostate. 2004; 59:409-18. https://doi.org/10.1002/pros.20001. PMid:15065089.

Von Schuckmann LA, Law MH, Montgomery GW, et al., Vitamin D pathway gene polymorphisms and keratinocyte cancers: A nested case-control study and meta-analysis. Anticancer Res. 2016; 36:2145-52.

Lee YH, Gyu Song G. Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: A meta-analysis. J BUON. 2015; 20:235-43.

Han J, Colditz GA, Hunter DJ. Polymorphisms in the MTHFR and VDR genes and skin cancer risk. Carcinogenesis. 2007; 28:390- 97. https://doi.org/10.1093/carcin/bgl156. PMid:16950800.

Hutchinson PE, Osborne JE, Lear JT, et al., Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma. Clin Cancer Res. 2000; 6:498-504.

Hajj A, Chedid R, Chouery E, et al., Relationship between vitamin D receptor gene polymorphisms, cardiovascular risk factors and adiponectin in a healthy young population. Pharmacogenomics. 2016; 17:1675-86. https://doi.org/10.2217/pgs-2016-0045. PMid:27672714.

He L, Wang M. Association of vitamin D receptor- A gene polymorphisms with coronary heart disease in Han Chinese. Int J Clin Exp Med. 2015; 8:6224-29.

Alizadeh S, Djafarian K, Alizadeh H, et al., Common variants of Vitamin D receptor gene polymorphisms and susceptibility to coronary artery disease: A systematic review and meta-Analysis. J Nutrigenet Nutrigenomics. 2017; 10:9-18. https://doi. org/10.1159/000455914. PMid: 28351026.

Bhalla AK, Amento EP, Serog B., Glimcher LH. 1,25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. J Immunol. 1984; 133:1748-54.

Bach JF. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev. 1994; 15:516-42. https://doi.org/10.1210/ edrv-15-4-516. PMid:7988484.

Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 1995; 53:599-602. https://doi. org/10.1016/0960-0760(95)00106-A.

Norman AW. The vitamin D endocrine system: identification of another piece of the puzzle. Endocrinology. 1994; 134:1601A-1601C. https://doi.org/10.1210/endo.134.4. 8137720. PMid:8137720.

McDermott MF, Ramachandran A, Ogunkolade BW, et al., Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians. Diabetologia. 1997; 40:971-75. https://doi.org/10.1007/s001250050776. PMid:9267994.

Motohashi Y, Yamada S, Yanagawa T, et al., Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes. J Clin Endocrinol Metab. 2003; 88:3137-40. https://doi.org/10.1210/jc.2002-021881. PMid:12843155.

Nejentsev S, Cooper JD, Godfrey L, et al., Analysis of the vitamin D receptor gene sequence variants in type 1 diabetes. Diabetes. 2004; 53:2709-12. https://doi.org/10.2337/diabetes.53.10.2709. PMid:15448105.

Angel B, Santos JL, Carrasco E, et al., Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in Chilean subjects: A case-parent study. Eur J Epidemiol. 2004; 19:1085-87. https://doi.org/10.1007/s10654-004-1026-z. PMid:15678787.

Chang TJ, Lei HH, Yeh JI, et al., Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population. Clin Endocrinol. 2000; 52:575-80. https://doi.org/10.1046/j.1365-2265.2000. 00985.x. PMid:10792336.

Turpeinen H, Hermann R, Vaara S, et al., Vitamin D receptor polymorphisms: No association with type 1 diabetes in the Finnish population. Eur J Endocrinol. 2003; 149:591-96. https://doi.org/10.1530/eje.0.1490591. PMid:14641002.

Fathy WM, Tawfeek GA, Tawfeek AR, Aboelyazeid SM. Vitamin D receptor ( BsmI ) gene polymorphism and type 2 diabetes mellitus in an Egyptian population. Menoufia Med J. 2018; 31:557-63.

Ortlepp JR, Lauscher J, Hoffmann R, et al., The vitamin D receptor gene variant is associated with the prevalence of Type 2 diabetes mellitus and coronary artery disease. Diabet Med. 2001; 18:842-45. https://doi.org/10.1046/j.1464-5491.2001.00585.x. PMid:11678976.

Hitman GA, Mannan N, McDermott MF, et al., Vitamin D receptor gene polymorphisms influence insulin secretion in Bangladeshi Asians. Diabetes. 1998; 47:688-90. https://doi.org/10.2337/diabetes.47.4.688. PMid:9568705.

Ye WZ, Reis AF, Dubois-Laforgue D, et al., Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset. Eur J Endocrinol. 2001; 145:181-86. https://doi.org/10.1530/eje.0.1450181. PMid:11454514.

Gnanaprakash V, Bodhini D, Kanthimathi S, et al., Association of Vitamin D receptor (TaqI, BsmI, and FokI) polymorphisms with prediabetes and Type 2 diabetes in Asian Indians. J Diabetol. 2019; 10: 29-36. https://doi.org/10.4103/jod.jod_14_18.

Nosratabadi R, Arababadi MK, Salehabad VA. Vitamin D Receptor Polymorphisms in Type 2 Diabetes in Southeastern Iranian Patients. Lab Med. 2011; 42:32-34 https://doi.org/10.1309/LMW788XEEYVVLBUV.

Angel B, Lera L, Márquez C, Albala C. The association of VDR polymorphisms and type 2 diabetes in older people living in community in Santiago de Chile. Nutr Diabetes. 2018; 8:31. https://doi.org/10.1038/s41387-018-0038-9. PMid:29795525 PMCid: PMC5968031.

Roth DE, Soto G, Arenas F, et al., Association between vitamin D receptor gene polymorphisms and response to treatment of pulmonary tuberculosis. J Infect Dis. 2004; 190: 920-27. https://doi.org/10.1086/423212. PMid:15295697.

Roy S, Frodsham A, Saha B, et al., Association of vitamin D Receptor genotype with leprosy type. J Infect Dis. 1999; 179: 187-91. https://doi.org/10.1086/314536. PMid:9841838.

Goulart LR, Ferreira FR, Goulart IMB. Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy. FEMS Immunol Med Microbiol. 2006; 48:91-98. https://doi. org/10.1111/j.1574-695X.2006.00128.x. PMid:16965356.

Mahyar A, Ayazi P, Afshar AS, et al., Vitamin D receptor gene (FokI, TaqI, BsmI, and ApaI) polymorphisms in children with urinary tract infection. Pediatr Res. 2018; 84:527-32. https://doi.org/10.1038/s41390-018-0092-y. PMid:29976973.

Simmons JD, Mullighan C, Welsh KI, et al., Vitamin D receptor gene polymorphism: Association with Crohn’s disease susceptibility. Gut. 2000; 47:211-14. https://doi.org/10.1136/gut.47.2.211. PMid:10896912 PMCid:PMC1728007.

Leon Rodriguez DA, Carmona FD, González CI, Martin J. Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy. Sci Rep. 2016; 6:1-6. https://doi.org/10.1038/srep31263. PMid:27502545 PMCid:PMC4977507.

Martins DJ, Matos GC, Loiola RS, et al., Relationship of vitamin D receptor gene polymorphisms in Helicobacter pylori gastric patients. Clin Exp Gastroenterol. 2018; 12:19-27. https://doi.org/10.2147/CEG.S143332. PMid:29391820 PMCid:PMC5769596.

Bellamy R, Ruwende C, Corrah T et al., Tuberculosis and chronic Hepatitis B virus infection in africans and variation in the vitamin D receptor gene. J Infect Dis. 2002; 179:721-24. https://doi.org/10.1086/314614. PMid:9952386.

Torres C, Sanchez-de-la-Torre M, Garcia-Moruja C, et al., Immunophenotype of Vitamin D receptor polymorphism associated to risk of HIV-1 infection and rate of disease progression. Curr HIV Res. 2010; 8:487-92. https://doi.org/10.2174/157016210793499330. PMid:20642435.

Han WG, Hodemaekers HM, Nagarajah B, et al., Association of vitamin D receptor polymorphism with susceptibility to symptomatic pertussis. PLoS One. 2016; 11:1-13. https://doi.org/10.1371/journal.,pone.0149576. PMid:26894582 PMCid:PMC4760950.

Dabirnia R, Mahmazi S, Taromchi A, et al., The relationship between Vitamin D Receptor (VDR) polymorphism and the occurrence of osteoporosis in menopausal Iranian women. Clin Cases Miner Bone Metab. 2017; 13(3):190-94. https://doi. org/10.11138/ccmbm/2016.13.3.190. PMid:28228780 PMCid:PMC5318170.

Nelson DA, Vande Vord PJ, Wooley PH. Polymorphism in the vitamin D receptor gene and bone mass in African-American and white mothers and children: A preliminary report. Ann Rheum Dis. 2000; 59(8):626-630. https://doi.org/10.1136/ard.59.8.626. PMid:10913060 PMCid:PMC1753219.

Zintzaras E, Rodopoulou P, Koukoulis GN, et al., BsmI, TaqI, ApaI and FokI polymorphisms in the Vitamin D Receptor (VDR) gene and the risk of osteoporosis: A meta-analysis. Dis Markers. 2006; 22:317-26. https://doi.org/10.1155/2006/921694. PMid:17264402 PMCid: PMC3851656.

Marozik PM, Tamulaitiene M, Rudenka E, Alenka V. Association of Vitamin D Receptor gene variation with osteoporosis risk in Belarusian and Lithuanian postmenopausal women. Front Endocrinol. 2018; 9:305. https://doi.org/10.3389/fendo.2018.00305. PMid:29922235 PMCid:PMC5996071.

Zhang Z-l, Zhao J-x, Meng X-w, et al., Association of polymorphisms of vitamin D receptor gene start codon and 3’-end region with bone mineral density in postmenopausal women. Chinese J Med Gen. 2003; 20:5-8.

Jia F, Wang D. Vitamin D Receptor Bsm I polymorphism and osteoporosis. Genet Test Mol Biomarkers. 2013; 17:30-34. https:// doi.org/10.1089/gtmb.2012.0267. PMid:23134477.

Liao J, Qin Q, Zhou Y et al., Vitamin D receptor Bsm I polymorphism and osteoporosis risk in postmenopausal women: A meta-analysis from 42 studies. Genes Nutr. 2020; 15: 20. https://doi.org/10.1186/s12263-020-00679-9. PMid:33238893 PMCid:PMC7687795.

Garrofé RF, Fornés CG, Montané MB, et al., Polymorphism of Vitamin D receptor gene, bone mass, and bone turnover among women with postmenopausal osteoporosis. Rev Clin Esp. 2000; 200:198-02.

Mansi JL, Thomas V, Carter N, Colston KW. Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population. Br J Cancer. 2001; 85:171-75. https://doi.org/10.1054/bjoc.2001.1864. PMid:11461072 PMCid:PMC2364044.

Chen WY, Bertone-johnson ER, Hunter DJ, et al., Associations between polymorphisms in the vitamin D receptor and breast cancer risk. Cancer Epidemiol Biomarker Prev. 2008; 14:2335-40. https://doi.org/10.1158/1055-9965.EPI-05-0283. PMid:16214913.

Trabert B, Malone KE, Daling JR et al., Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women. Breast Cancer Res. 2007; 9:1-10. https://doi.org/10.1186/bcr1833. PMid:18067661 PMCid:PMC2246187.

Zhang K, Song L. Association between vitamin D receptor gene polymorphisms and breast cancer risk: A meta-analysis of 39 Studies. PLoS One. 2014;9(4). https://doi.org/10.1371/journal.,pone.0096125. PMid:24769568 PMCid:PMC4000223.

Ntais C, Polycarpou A, Ioannidis JPA. Vitamin D receptor gene polymorphisms and risk of prostate cancer: A meta-analysis. Cancer Epidemiol Biomarker Prev. 2003; 12:1395-02.

Berndt SI, Dodson JL, Huang W, Nicodemus KK. Gene polymorphisms and prostate cancer risk. J Urol. 2006; 175:1613-23 https:// doi.org/10.1016/S0022-5347(05)00958-4.

Shen Y. Polymorphisms of vitamin D receptor gene TaqI susceptibility of prostate cancer: A meta-analysis. Onco Targets Ther. 2016; 9:1033-45. https://doi.org/10.2147/OTT.S99428. PMid:27042096 PMCid:PMC4780196.

Liu Y, Li C, Chen P, et al., Polymorphisms in the Vitamin D Receptor (VDR) and the risk of ovarian cancer: A meta-analysis. PLoS One. 2013; 8:1-8. https://doi.org/10.1371/journal.,pone.0066716. PMid:23826116 PMCid:PMC3691226.

Tamez S, Norizoe C, Ochiai K, et al., Vitamin D receptor polymorphisms and prognosis of patients with epithelial ovarian cancer. Br J Cancer. 2009; 101:1957-60. https://doi.org/10.1038/sj.bjc.6605414. PMid:19904266 PMCid: PMC2777264.

Mohapatra S, Saxena A, Gandhi G, et al., Vitamin D and VDR gene polymorphism (FokI) in epithelial ovarian cancer in Indian population. J Ovarian Res. 2013; 6:2-7. https://doi.org/10.1186/1757-2215-6-37. PMid:23705897 PMCid:PMC3668239.

Pan Z, Chen M, Hu X, et al., Associations between VDR gene polymorphisms and colorectal cancer susceptibility: An updated meta-analysis based on 39 case-control studies. Oncotarget. 2018; 9:13068-76. https://doi.org/10.18632/oncotarget.23964. PMid:29560132 PMCid:PMC5849196.

Bai YH, Lu H, Hong D, et al., Vitamin D receptor gene polymorphisms and colorectal cancer risk: A systematic meta-analysis. World J Gastroenterol. 2012; 18:1672-79. https://doi.org/10.3748/wjg.v18.i14.1672. PMid:22529698 PMCid:PMC3325535.

Tekand, Y., Toptas, B. Association of vitamin D receptor gene polymorphisms with colon cancer. Genet Test Mol Biomarkers. 2012; 16:1058-61. https://doi.org/10.1089/gtmb.2012.0044. PMid:22852885.

Zhao X-Z, Yang B-H, Yu G-H, et al., Polymorphisms in the Vitamin D Receptor (VDR) genes and skin cancer risk in European population: A meta-analysis. Arch Dermatol Res. 2014; 306(6):545-53. https://doi.org/10.1007/s00403-014-1464-8. PMid:24771013.

Burns EM, Guroji P, Ahmad I, et al., Association of vitamin D receptor Polymorphisms with the risk of nonmelanoma skin cancer in adults. JAMA Dermatol. 2017; 153(10):983-89. https://doi.org/10.1001/jamadermatol.2017.1976. PMid:28832880 PMCid:PMC5710406.

Santonocito C, Capizzi R, Concolino P, et al., Association between cutaneous melanoma, Breslow thickness and vitamin D receptor Bsm I polymorphism. Br J Dermatol. 2007; 156(2):277-82. https://doi.org/10.1111/j.1365-2133.2006.07620.x. PMid:17223867.

Apayd?n M, Beysel S, Eyerci N, et al., The VDR gene FokI polymorphism is associated with gestational diabetes mellitus in Turkish women. BMC Medical Genetics. 2019; 20:82. https://doi.org/10.1186/s12881-019-0820-0. PMid:31096931 PMCid:PMC6524275.

Sarma D., Chauhan V. S., Saikia K. K., et al., Prevalence Pattern of key polymorphisms in the vitamin D receptor gene among patients of Type 2 diabetes mellitus in Northeast India. Indian J Endocr Metab. 2018; 22(2):229-35. https://doi.org/10.4103/ijem. IJEM_213_17. PMid:29911037 PM Cid:PMC5972480.

Goulart LR, Ferreira FR, Goulart IMB. Interaction of TaqI polymorphism at exon 9 of the vitamin D receptor gene with the negative lepromin response may favor the occurrence of leprosy. FEMS Immunol Med Microbiol. 2006; 48:91-98. https://doi. org/10.1111/j.1574-695X.2006.00128.x. PMid:16965356.

Singh I, Lavania M, Pathak VK, et al., VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population. PLoS Negl Trop Dis. 2018; 12:1-14. https://doi.org/10.1371/journal.,pntd.0006823. PMid:30481178 PMCid:PMC6286024.

Neela VS, Suryadevara NC, Shinde VG, et al., Association of Taq I, Fok I and Apa I polymorphisms in Vitamin D Receptor (VDR) gene with leprosy. Hum Immunol. 2015; 76:402-05 . https://doi.org/10.1016/j.humimm.2015.04.002. PMid:25890006.

Kang TJ, Jin SH, Yeum CE, et al., Vitamin D receptor gene Taq I, Bsm I and Fok I polymorphisms in Korean patients with tuberculosis. Immune Netw. 2011; 11:253-57. https://doi.org/10.4110/in.2011.11.5.253. PMid:22194708 PMCid:PMC3242999.

Cao Y, Wang X, Cao Z, Cheng X. Vitamin D receptor gene FokI polymorphisms and tuberculosis susceptibility: A meta-analysis. Arch Med Sci. 2016; 12:1118-34. https://doi.org/10.5114/aoms.2016.60092. PMid:27695504 PMCid: PMC5016579.

Panda S, Tiwari A, Luthra K, et al., Association of Fok1 VDR polymorphism with Vitamin D and its associated molecules in pulmonary tuberculosis patients and their household contacts. Sci. Rep. 2019; 9:1-10. https://doi.org/10.1038/s41598-019-51803- 8. PMid:31649297 PMCid: PMC6813333.

Leon Rodriguez DA, Carmona FD, González CI, Martin J. Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy. Sci. Rep. 2016; 6:1-6. https://doi.org/10.1038/srep31263. PMid:27502545 PMCid:PMC4977507.

Oliveira LR, Carvalho TB, Santos RM, et al., Association of vitamin D3, VDR gene polymorphisms, and LL-37 with a clinical form of Chagas disease. Rev Soc Bras Med Trop. 2019; 52:1-10. https://doi.org/10.1590/0037-8682-0133-2019. PMid:31508781.

Shabandoust H, Sharifi I, Raiesi O, et al., Serum 25-hydroxyvitamin D level and Vitamin D Receptor (VDR) polymorphisms in patients infected with Leishmania tropica: A case control study. J Parasit Dis. 2019; 44(1):40-48. https://doi.org/10.1007/s12639- 019-01159-7. PMid: 32174704 PMCid:PMC7046910.

Aslan S, Akil I, Aslan G, et al., Vitamin D receptor gene polymorphism in children with urinary tract infection. Pediatr Nephrol. 2012; 27:417-21. https://doi.org/10.1007/s00467-011-2000-0. PMid:21947233.

Hassanein SI, Sleem HM, Gad MZ. Vitamin D receptor gene polymorphisms (TaqI and ApaI) in relation to 25-hydroxyvitamin D levels and coronary artery disease incidence. J Recept Signal Transduct Res. 2015; 35:391-95. https://doi.org/10.3109/1079989 3.2014.959593. PMid: 25224407.

Marazuela M. Endocrine and metabolic aspects of the COVID-19 pandemic. Rev Endocr Metab Disord. 2020; 21: 495-07. https:// doi.org/10.1007/s11154-020-09569-2. PMid:32643004 PMCid:PMC7343578.

Greiller CL., Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015; 7:4240-70. https://doi.org/10.3390/nu7064240. PMid:26035247 PMCid:PMC4488782.

Bilezikian JP, Bikle D, Hewison M, et al., Vitamin D and COVID-19. Eur J Endocrinol. 2020; 183:133-47. https://doi.org/10.1530/ EJE-20-0665. PMid:32755992.

Martineau A, Jolliffe D, Hooper R, et al., Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ. 2017; 356:6583 https://doi.org/10.1136/bmj.i6583. PMid:28202713 PMCid: PMC5310969.

Mohan M, Cherian JJ., Sharma A. Exploring links between Vitamin D deficiency and covid-19. PLoS Pathog. 2020; 16(9):e1008874. https://doi.org/10.1371/journal.,ppat.1008874. PMid:32946517 PMCid:PMC7 500624.

Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer outcome? Lancet Diabetes Endocrinol. 2020; 8:570. https://doi. org/10.1016/S2213-8587(20)30183-2.

Hastie CE, Mackay DF, Ho F, et al., Vitamin D concentrations and COVID-19 infection in UK Biobank. Diab Metab Syndr. 2020; 14:561-65 https://doi.org/10.1016/j.dsx.2020.04.050. PMid:32413819 PMCid:PMC7204679.

Annweiler C, Hanotte B, de l’Eprevier CG, et al., Vitamin D and survival in COVID-19 patients: A quasi-experimental study. J Steroid Biochem Mol Biol. 2020; 204:1-6 . https://doi.org/10.1016/j.jsbmb.2020.105771. PMid:33065275 PMCid:PMC7553119.

Jolliffe DA, Greiller CL, Mein CA, et al., Vitamin D receptor genotype influences risk of upper respiratory infection. Br J Nutr. 2018; 120:881-90. https://doi.org/10.1017/S000711451800209X. PMid:30132432.

Grant WB, Lahore H, McDonnell SL, et al., Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020; 12:1-19. https://doi.org/10.20944/preprints202003.0235.v2.

Radujkovic A, Hippchen T, Tiwari-Heckler S, et al., Vitamin D deficiency and outcome of COVID-19 patients. Nutrients. 2020; 12(9):2757. https://doi.org/10.3390/nu12092757. PMid:32927735 PMCid:PMC7551780.

Panfili FM, Roversi M, D’argenio P, et al., Possible role of vitamin D in Covid-19 infection in pediatric population. J Endocrinol Invest. 2021; 44:27-35. https://doi.org/10.1007/s40618-020-01327-0. PMid:32557271 PMCid:PMC7299247.