CURATED IN
31.7 %
OF CURATIONS
| | TYPICAL |
| IMPUTED THERAPY |
| STIMULATE |
| ★★★★★ |
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VDR
Label: vitamin D (1,25- dihydroxyvitamin D3) receptor
Aliases: NR1I1,PPP1R163
Location:12q13.11
Show client (simplified) description
Client Description: The VDR gene provides instructions for making a protein called vitamin D receptor (VDR), which allows the body to respond appropriately to vitamin D. This vitamin can be acquired from foods in the diet or made in the body with help from sunlight. Vitamin D is involved in maintaining the proper balance of several minerals in the body, including calcium and phosphate, which are essential for the normal formation of bones and teeth. One of vitamin D's major roles is to control the absorption of calcium and phosphate from the intestines into the bloodstream. Vitamin D is also involved in several process unrelated to bone formation. VDR attaches (binds) to the active form of vitamin D, known as calcitriol. This interaction allows VDR to partner with another protein called retinoid X receptor (RXR). The resulting complex of proteins then binds to particular regions of DNA, known as vitamin D response elements, and regulates the activity of vitamin D-responsive genes. By turning these genes on or off, VDR helps control calcium and phosphate absorption and other processes. A VDR variant FokI is involved with Blood sugar regulation. Certain VDR mutations oppose COMT mutations in the regulation of dopamine levels. A VDR TaqI++ mutation means that a person is less sensitive to mood swings when taking methyl group supplement levels. A VDR Taq1 mutation can result in behaviors opposite to certain COMT mutations. The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals. Glucocorticoids are known to decrease expression of VDR, which is expressed in most tissues of the body and regulate intestinal transport of calcium, iron and other minerals. The VDR BsmI variant has been associated with low bone mineral density and osteoporosis. Mutations in the VDR gene cause vitamin D-dependent rickets type 2 (VDDR2), also known as hereditary vitamin D-resistant rickets (HVDRR). This disorder of bone development is characterized by low levels of calcium (hypocalcemia) and phosphate (hypophosphatemia) in the blood, which lead to soft, weak bones (rickets) that are prone to fracture. A common feature of this condition is bowed legs. The VDR gene mutations that cause this condition prevent the VDR protein from functioning properly. Some changes in the VDR gene lead to an abnormally short version of the VDR protein; others result in the production of an abnormal receptor that cannot bind to calcitriol, to RXR, or to DNA. Despite plenty of calcitriol in the body, the altered VDR cannot stimulate gene activity important for mineral absorption. The lack of calcium and phosphate absorption in the intestines slows deposition of these minerals into developing bone (bone mineralization), which leads to soft, weak bones and other features of VDDR2. Hypocalcemia also causes muscle weakness and seizures in some affected individuals. Most VDR gene mutations impair hair growth, leading to alopecia; however, mutations that block VDR's ability to interact with calcitriol do not cause alopecia, indicating that calcitriol is not necessary for the receptor's role in hair development.
This gene encodes the nuclear hormone receptor for vitamin D3. This receptor also functions as a receptor for the secondary bile acid lithocholic acid. The receptor belongs to the family of trans-acting transcriptional regulatory factors and shows sequence similarity to the steroid and thyroid hormone receptors. Downstream targets of this nuclear hormone receptor are principally involved in mineral metabolism though the receptor regulates a variety of other metabolic pathways, such as those involved in the immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternative splicing results in multiple transcript variants encoding different proteins. VDR gene encodes the nuclear hormone receptor for 1α,25-(OH)2 D3. This receptor also functions as a receptor for the secondary, (produced by Clostridia spp.), bile acid(1) lithocholic acid (LCA). Upon exposure VDR stimulates CYP3A to metabolize LCA, which if not detoxified is liver toxic and carcinogenic to the intestines (2). The active form, 1,25(OH)2D3 further enhances VDR’s genomic actions and regulates the expression of several dopaminergic-associated genes. Also, 1,25(OH)2D3 upregulates COMT expression as well as its direct product the DA metabolite 3-MT. Furthermore, 1,25(OH)2D3 enhances VDR binding to VDREs within the COMT promoter strongly suggesting direct regulation. 93) Hence, in relation to the COMT(rs4680) homozygous normal allele and VDR Taq1 homozygous risk allele = Lowest dopamine production, poorest tolerance to toxins and microbes. This type needs and tolerates dopamine precursors and methyl donors and would have the lowest susceptibility to mood swings. In relation to COMT homozygous risk allele and VDR Taq1 homozygous normal allele, this combination would have the highest dopamine production, with better tolerance to toxins and microbes. There would be reduced need for and reduced tolerance to dopamine precursors and methyl donors and would have the greatest susceptibility to mood swings.(4)
Targets of Vitamin D Receptor (VDR) are principally involved in mineral metabolism though the receptor regulates a wide variety of other metabolic pathways by expression and repression of many genes. Examples are those involved in the immune response of thyroiditis, diabetes by modulating CD4 lymphocyte, the autoimmune activity of TH1, by reducing production of IL-2, IFN-g, and TNF-a. At the same time VDR upregulates TH2 cells to secrete IL4 and IL10 cytokines (5).
Upon activation by 1α,25-(OH)2 D3, the VDR binds to hormone response elements (VDRE) with PXR and RXR on DNA resulting in expression or repression of many specific gene products. VDR inhibits the expression of cancer combining 1α,25-(OH)2 D3 and retinoic acid sensitizing growth inhibition (6).
VDR is involved in regulates steroid and drug metabolism by inducing the genes encoding phase I and phase II enzymes including: CYP1A2, CYP3A, CYP1B1, SULT2A1(4).
VDR FOKI mutation decreases dopamine formation via reduced effect on dopamine receptor D1(7). The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals. Glucocorticoids are known to decrease expression of VDR, which is expressed in most tissues of the body and regulate intestinal transport of calcium, iron and other minerals. VDR SNP rs1544410 has been associated with low bone mineral density and osteoporosis. References: - Ridlon JM, Bajaj JS. The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics. Acta Pharm Sin B. 2015 Mar;5(2):99-105. doi:10.1016/j.apsb.2015.01.006. Epub 2015 Feb 9. Review. [PMID: 26579434].
- Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ. Vitamin D receptor as an intestinal bile acid sensor. Science.2002 May 17;296(5571):1313-6. [PMID: 12016314].
- Pertile RA, Cui X, Eyles DW. Vitamin D signaling and the differentiation of developing dopamine systems. Neuroscience. 2016 Oct 1;333:193-203. doi: 10.1016/j.neuroscience.2016.07.020. Epub 2016 Jul 20. PubMed PMID: 27450565.
- Stein DJ, Newman TK, Savitz J, Ramesar R. Warriors versus worriers: the role of COMT gene variants. CNS Spectr. 2006 Oct;11(10):745-8. DOI: 10.1017/s1092852900014863. PubMed PMID: 17008817.
- Christakos S, Dhawan P, Liu Y, Peng X, Porta A. New insights into the mechanisms of vitamin D action. J Cell Biochem. 2003 Mar 1;88(4):695-705. Review. [PMID: 12577303].
- Song CS, Echchgadda I, Seo YK, Oh T, Kim S, Kim SA, Cho S, Shi L, Chatterjee B. An essential role of the CAAT/enhancer binding protein-alpha in the vitamin D-induced expression of the human steroid/bile acid sulfotransferase (SULT2A1). Mol Endocrinol. 2006 Apr;20(4):795-808. Epub 2005 Dec 15. Erratum in: Mol Endocrinol. 2006 Jun;20(6):1286. [PMID: 16357103].
- Ahmadi S, Mirzaei K, Hossein-Nezhad A, Shariati G. Vitamin D receptor FokI genotype may modify the susceptibility to schizophrenia and bipolar mood disorder by regulation of dopamine D1 receptor gene expression. Minerva Med. 2012 Oct;103(5):383-91. [PMID: 23042374].
VDR DOWN-REGULATION In an essay on the renin–angiotensin system (RAS) and immune response, Smith postulated that unresolved cellular stress may be caused by infectious agents to avoid adaptive immune responses. The host immune response has developed many mechanisms to neutralize and remove pathogenic bacteria. In turn, pathogenic bacteria have developed mechanisms to alter and evade the host immune response. Regulation of the VDR is a common mechanism used in the host defense against pathogens but certain microbes have been shown to slow innate immune defenses by down-regulating the VDR: - Mycobacterium tuberculosis down-regulates VDR activity.
- Mycobacterium leprae inhibits VDR activity through down-regulation of CYP27B1 in monocytes.
- Aspergillus fumigatus secretes a toxin capable of down-regulating the VDR in macrophages.
- Epstein–Barr virus lowers VDR activity.
- HIV completely shuts down VDR activity.
- In VDR knockout mice, a circumstance that closely mimics extreme VDR dysregulation, 1,25(OH)2D levels increase by a factor of ten.
- Studies also point to immune system depression and elevated 1,25(OH)2D in chronic diseases:
- Sarcoidosis patients are deficient in cathelicidin despite healthy vitamin D3 levels.
- 1,25(OH)2D is high (>60 pg/ml) in 42 % of Crohn’s patients and the source of the active vitamin D may be the inflamed intestine.
- 1,25(OH)2D is elevated in the synovial fluid of patients with RA (rheumatoid arthritis).
- Crohn’s disease decreases expression of cathelicidin.
Some authorities now believe that low 25(OH)D is a consequence of chronic inflammation rather than the cause. Research points to a bacterial etiology pathogenesis for an inflammatory disease process which results in high 1,25(OH)2D and low 25(OH)D. Immunotherapy, directed at eradicating persistent intracellular pathogens, corrects dysregulated vitamin D metabolism and resolves inflammatory symptoms. Reference: - Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the infection connection. Inflamm Res. 2014 Oct;63(10):803-19. doi: 10.1007/s00011-014-0755-z. [PMID: 25048990]
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Genetic Disease(s) linked to VDR
Naturopathic Agents Known to Influence Expression of VDR:
HapMap Distribution