Receptory vitamínu D

Calcitriol receptor - vitamin D receptor - VDR

• Součástí velké rodiny steroidních nukleárních receptorů of over 150 members -nuclear hormone receptor
• Glukokortikoidy
• Tyreoidální hormony
• Pohlavní hormony
• Retinoidy
• Mastné kyseliny
• Eikosanoidy [6]
• bile acids
• Isoprenoids [22]
• Nuclear receptor superfamily of steroid/thyroid hormone receptors
• Large number of family members have no known ligands
• Orphan receptors [22]

Struktura VDR

• Cca 50-60kDa depending on species
• Very short N-terminal domain before the DNA binding domain
• Compared to other nuclear hormone receptors
• Human VDR has two potential start sites
• Most conserved domain in VDR is the DNA binding domain
• Comprised of two zinc fingers
• Cysteines within this stretch of amino acids that form tetrahedral complexes with zinc in a manner which creates a loop or finger of amino acids with the zinc complex at its base
• Proximal (N-terminal) zinc finger
• Confers specificity for DNA binding to the VDREs [22]
• Second zinc finger and the region following
• At least one of the sites for heterodimerization of the VDR to the retinoid X receptor (RXR) [22]
• Second half of the molecule
• Ligand binding domain for binding 1,25(OH)2D
• Regions necessary for heterodimerization to RXR [22]
• C-terminal end
• Major activation domain, AF-2
• Critical for the binding to coactivators
• Such as those in the steroid receptor coactivator (SRC)
• vitamin D receptor interacting protein (DRIP)
• Mediator families [22]

VDR předávání signálu - genomické

• Ovlivňuje transkripci cca 5 % lidského genomu [6]

VDR v buňce

• Unbound inactive form of the calcitriol receptor resides in the cytoplasm
• RXR pomáhají udržet jeho existenci v bu. bez navázaného vit. D

Calcitriol binds to the receptor

Fosforylace of the VDR

• May also control VDR function
• VDR has been shown to suppress b-catenin transcriptional activity
• B-catenin enhances that of VDR
• Control of VDR activity
• Involve crosstalk between signaling pathways originating in receptors at the plasma membrane as well as within the nucleus.

Heterodimerizace

• With other nuclear hormone receptors, in particular the family of retinoid X receptors
• Complex formation with the RXR (Mora et al., 2008; Christakos et al., 2016)
• This increases the affinity of the VDR/RXR complex for the vitamin D response element (VDRE), a specific sequence of nucleotides in the promoter region of the vitamin D responsive gene [22]

RXR

• There are three forms of RXR
• Alpha,beta, gamma
• All three are capable of binding to VDR
• RXR and VDR form heterodimers
• RXR is the rule
• Optimize their affinity for the vitamin D response elements (VDREs)
• RXR appears to be responsible for keeping VDR in the nucleus in the absence of ligand
• RXR binds to the upstream half site
• VDR binds to the downstream site
• Wide range of VDRE configurations have been found at nearly any location within a gene (5’, 3’, introns)
• Different tissues differ as to which VDREs actively bind VDR
• 1,25(OH)2D is required for high affinity binding and activation
• RXR ligand - 9-cis retinoic acid
• may either inhibit or activate 1,25(OH)2D stimulation of gene transcription

Thyroid receptors

• VDR may also partner with other receptors
• Thyroid receptor (TR)

Retinoic acid receptor (RAR)

• Vjymečně se VDR spojí i s RAR

• hraje pak roli, zda je navázán vit. A nebo není - různý výsledek !!

Translokace do jádra

• Ligand-receptor complex translocates to the cell nucleus

Vazba na DNA - Vitamin D response element (VDRE)

• In the presence of 1,25D3, the VDR/RXR complex interacts with a consensus DNA region
• Acts as a transcription factor promoting the expression of a gene
• Modulates the transcription of specific genes (Mora et al., 2008; Christakos et al., 2016) [12]

Různé VDREs

• There are thousands of the VDREs in hundreds of genes
• Profile of active VDREs (and regulated genes) varies from cell to cell [22]

Koregulační molekuly

• Variety of additional coregulators complex of VDR transcriptional activity
• Binding VDR/RXR complex to the VDRE attracts a complex of coactivators to the VDR/RXR complex

Coactivators

• Steroid Receptor Coactivator family (SRC 1-3)
• SRC recruit histone acetyl transferases (HAT) and demethylases (DME) to the gene promoting the opening up of its structure [22]
• To enable the transcription machinery to work
• Transcription of the gene is initiated to produce the corresponding mRNA
• Leaves the nucleus to be translated to the corresponding protein [22]
• SRC family has three members
• SRC 1-3
• All bind to the VDR in the presence of (1,25(OH)2D)
• Recruit additional coactivators such as
• CBP/p300
• P/CAF
• Have histone acetyl transferase activity (HAT)
• Acetylation of lysines within specific histones
• Help unravel the chromatin allowing the transcriptional machinery
• NR box domain- critical for binding to the VDR and other nuclear hormone receptors
• Central motif LxxLL
• L stands for leucine
• X for any amino acid
• Each SRC family member contains three well conserved NR boxes
• SMAD 3
• A transcription factor in the TGF-beta pathway
• Complex with the SRC family members and the VDR
• Enhancing the coactivation process [22]

• D Receptor Interacting Protein complex - DRIP - Mediator coactivator complex - The DRIP (Mediator) complex
• Form a bridge:
• VDR binding - VDRE - RNA polymerase II at the transcription start site - other proteins in the initiation complex [22]
• Centered at or around the TATA box
• Or other transcription regulatory elements [22]
• 15 or so proteins
• Contain LxxLL motifs
• DRIP205 (Mediator 1)
• protein critical for binding the complex to VDR
• Contains 2 NR boxes
• Different NR boxes in these coactivators
• Specificity for different nuclear hormone receptors
• DRIP complex
• Does not have HAT activity
• Spans the gene from the VDRE to the transcription start site
• Linking directly with RNA polymerase II and its associated transcription factors

• DRIP and SRC appear to compete for binding to the VDR
• In keratinocytes
• DRIP binds preferentially to the VDR in undifferentiated cells
• SRC 2 and 3 bind in the more differentiated cells in which DRIP levels have declined
• DRIP appears to regulate the early stages of 1,25(OH)2D induced differentiation
• SRC may be more important in the later stages

Corepressors [22]

• Hairless
• In the skin
• Loss or mutation, like that of the VDR
• Altered hair follicle cycling resulting in baldness [22]
• May regulate
• 1,25(OH)2D mediated epidermal proliferation and differentiation
• Ligand independent VDR regulation of hair follicle cycling [22]

• Recruiting histone deacetylases (HDAC) or methyl transferases (MT)
• To the gene which reverses the actions of HAT and DME
• Reduction in access to the gene by the transcription machinery [22]

• Can be specific for different genes
• Case different cells differentially express
• Specificity for the actions of 1,25(OH)2D and VDR [22]

Změna exprese nějakého proteinu vlivem působení vit. D

Direct inhibition of gene transcription

• Binding of the VDR to negative VDREs
• PTH and PTHrP genes are remarkably similar in sequence to positive VDREs of other genes

Indirect inhibition

• Inhibits IL-2 production
• By blocking the NFATp/AP-1 complex of transcription factors from activating this gene [22]
• Inhibits CYP27B1
• In at least one renal cell line by an indirect mechanism involving VDR binding to VDIR [22]

Předání signálu - ne-genomické

• Rapid effects on selected cells
• Not likely to involve gene regulation
• Appear to be mediated by a different, probably membrane receptor/channel [22]
• calcium channel activity
• Chloride channel activity
• protein kinase C activation and distribution
• Phospholipase C activity
• In a number of cells including
• Osteoblasts
• Liver
• Muscle
• Intestine[22]
• Most extensively studied [22]

• 1,25(OH)2D - membrane receptor - activate phospholipase C
• Possibly via G protein coupled process
• Phospholipase C then hydrolyzes phosphatidyl inositol bis phosphate (PIP2) in the membrane
• Releasing inositol tris phosphate (IP3) and diacyl glycerol (DG)
• May then activate both the intracellular release of calcium from intracellular stores
• Stimulate calcium channel activity
• Further rise in intracellular calcium levels
• In the intestine and kidney the increased flux of calcium across the brush border membrane
• Transported out of the cell at the basolateral membrane
• Completing transcellular transport [22]

• In other cells the increased calcium
• Need to be removed by other mechanisms [22]

Střevo

• Rapid onset of calcium flux across the intestine of a vitamin D replete chick perfused with 1,25(OH)2D
• Could not be blocked with actinomycin D pretreatment
• Was blocked by
• Voltage gated L type channel inhibitors
• protein kinase C inhibitors [22]
• Animals had to be
• vitamin D replete
• Contain the VDR [22]

• L type channel activators such as
• BAY K-8644
• protein kinase C activators such as phorbol esters
• Could activate transcaltachia similar to 1,25(OH)2D [22]

• Pokud ve střevě chybí vápník, hořčík, zinek ap. minerály, nasaje tento zvýšený transport hliník, olovo, fluoridy, rtuť,....všechno ostatní co může

Výskyt receptorů pro vitamín D (VDR) - 1,25–dihydroxycholekalciferol

• Střeva
• Ledviny
• Kost
• Kůže
• lymfocyty
• Monocyty
• Kosterní a srdeční sval
• Mléčná žláza [6] [11]
• Adenohypofýza
• Brain
• Heart
• Gonads
• Prostate [11]
• Keratinocytes [12]
• Fibroblasts [12]
• Monocytes [12]
• T lymphocytes (Bouillon et al., 2008) [12]
• Přítomen na všech buňkách imunitního systému, zvláště na:
• Profesionálních antigen prezentujících buňkách
• Makrofázích [6] [12]
• Dendritických buňkách [6] [12]
• Aktivovaných T-lymfocytech [6]
• V těle prakticky všude

Regulace VDR 25-D x 1,25-D

• Compete for nuclear receptors
• Opposing roles in the body !!! [22]

• VDR is foremost a control system
• Active form, 1,25-D = “on” switch
• Inactive form, 25-D = “off” switch [22]

• Binding affinities for the VDR
• 1,25-D - 8.48 (nanomolar Kd)
• 25-D - 8.36 (nanomolar Kd)
• Activation of the Vitamin D nuclear receptor
• Delicate balance between the concentrations of a number of endogenous hormones [22]

1,25-D

• Possesses a single 1-alpha hydroxylation
• Stabilizes helix 12 in the Vitamin D Receptor
• Binding the promoter which allow activation of the VDR
• Leads to the transcription of thousands of genes [22]

25-D

• Not completely inactive
• Cannot activate the VDR
• 25-D levels are not associated with
• Cathelicidin
• Beta-defensin-2 etc. [22]

Příklad regulace

Injury and infection enhances production of 1,25-D

• Creation of antimicrobial peptides
• Activation of TLR2 [22]
• High levels of 1,25-D and the enzyme which leads to the production of 1,25-D, 1 aplpha-hydroxylase
• Found at various locations where the human body needs a strong host defense

Aktivace inhibice - Feedback mechanisms

• Limit the production of 1,25-D
• VDR is activated
• Transcribes the gene for the enzyme CYP24A1
• Increases conversion of 1,25-D into inactive metabolites.
• Limiting transcription of the gene CYP27B1
• Which converts 25-D into 1,25-D [22]

Inhibice VDR

Stimulace VDR zvýšená

Exprese VDR snížená

Zvýšená exprese VDR

Aktivací Th CD4

• Exprese VDR na odpočívajících T-pomocných lymfocytech CD4
• se po aktivaci zpětinásobí [6]

Inactivating mutations in the VDR

Hereditary vitamin D resistant rickets (HVDRR)

Animal models of knocked out VDR

• Full phenotype of severe vitamin D deficiency
• VDR is the major mediator of vitamin D action [22]
• Alopecia seen in HVDRR and VDR knockout animals
• Not associated with vitamin D deficiency
• VDR may have functions independent of 1,25(OH)2D at least in hair follicle cycling [22]

Mice without a VDR

• Born with alopecia
• Inflammatory condition in which organisms have no hair
• Age prematurely
• Salmonella is much more virulent and aggressive
• Higher levels of activity of inflammatory molecules
• Lost weight more quickly
• Much more likely to die in response to infection [23]
• 10x vzestup 1,25-D
• Almost undetectable levels - in serum 25-D
• Persisted at seven weeks until the mice eventually died
• vitamin D and the VDR are not critical for skeletal formation
• Rickets develops postnatally
• Most manifest after weaning
• Impairment of endochondral bone formation
• Decreased alkaline phosphatase activity of the hypertrophic chondrocytes
• Alterations in the lipid composition of the matrix
• Perhaps secondary to reduced phospholipase activity
• Altered proteoglycan degradation
• Changes in metalloproteinase activity
• 1,25(OH)2D and 24,25(OH)2D
• Appear to be required for optimal endochondral bone formation
• VDR null mice become osteoporotic
• Despite the high calcium/phosphate diet [22]
• Rickets resulting from vitamin D deficiency or VDR mutations (or knockouts)
• Can be corrected by supplying adequate amounts of calcium and phosphate
• By infusions or orally
• Deletion of VDR from bone cells
• Does not result in rickets
• vitamin D metabolites do not directly impact bone
• Substantial redundancy has been built into the system.
• Development of osteoporosis
• Decreased bone formation in these VDR or CYP27B1 null mice
• Not corrected by the high calcium/phosphate diet
• Osteoblasts from VDR knockout mice
• Fail to support 1,25(OH)2D induced osteoclastogenesis
• Can be induced by 1,25(OH)2D in the presence of osteoblasts from wildtype animals
• Myelopoeisis and the composition of lymphoid organs are normal
• Number of abnormalities in the immune response have been found
• Some of the abnormalities in macrophage function and T cell proliferation
• In response to anti-CD3 stimulation could be reversed by high calcium diet to normalize serum calcium
• Skeletal development and maintenance
• Hormone regulation
• Keratinocyte differentiation [24]

• Increased number of mature DCs in the lymph nodes of VDR null mice
• Would be expected to promote the adaptive immune response
• Surprisingly, RANKL also increases the number and retention of DCs in lymph nodes [24]
• Th2 function indicated by increased IgE stimulated histamine from mast cells is increased in VDR null mice [24]

• IL-10 null mouse model of IBD
• Accelerated disease profile when bred with the VDR null mouse
• With increased expression of Th1 cytokines [24]
• Despite a reduction in natural killer T cells and Treg cells
• Decreased number of mature DCs, VDR null mice bred with NOD mice do not show accelerated development of diabetes [24]

• Method of inducing asthma
• Lack of VDR also protected the mice from an inflammatory response in their lungs
• Impact of vitamin D signaling on adaptive immunity depends on the specifics of the immune response being evaluated.

• Mouse null for VDR is protected
• Leishmania major
• Toxoplasmosis

Polymorfismy VDR

• Zvýšené riziko mnohočetných autoimunitních onemocnění:
• Hashimotovy tyreoditidy
• GB tyreotoxikózy
• Diabetes mellitus 1. typu
• Addisonovy choroby
• Revmatoidní artritidy
• Systémového lupus erythematodes
• Primární biliární cirhózy
• Autoimunitní hepatitidy
• Vitiliga
• Celiakie
• Zánětlivých puchýřnatých kožních onemocnění
• Sclerosis multiplex [6]

RS11574143 (VDR) CC

• SelfDecode test
• Importance: 3

Minor Allele: T = 12%

Major Allele: C = 88%

• Increased risk of prostate cancer
• Only in men with lower D3 protein levels
• Health Professionals Follow-up Study
• Risks tended also to be increased with carriage of the C allele, regardless of D3 levels
• SNPS in this region have been linked to higher VDR mRNA stability
• Higher gene transcription activity in some but not all in vitro studies
• Minor allele of this SNP may increase levels of VDR protein

• www.selfdecode.com/snp/rs11574143/

RS1540339 (VDR) CC

• SelfDecode test

RS1544410 (VDR) CT

• SelfDecode test
• Importance: 3

Minor Allele: T = 30%

• Lower bone density
• Presumably less VDR activity
• Decreased levels of VDR
• Decreased breast cancer risk

Major Allele: C = 70%

• Higher breast cancer risk in 5/9 studies done (CC)
• Women with CC
• Who consumed more than the median level of calcium
• Had lower breast cancer rates
• Who had low vitamin D3 levels
• 6.8-fold increase in breast cancer risk
• Increased risk of Graves' disease in the Polish population (p = 0.0070) [29]
• BsmI (intronic G›A replacement, C = b)

RS2107301 (VDR) GG

• SelfDecode test
• Importance: 2

Minor Allele: A = 34%

• AA= 2.5X prostate cancer risk
• Could not be replicated

Major Allele: G = 66%

RS2228570 (VDR) AG - VDR FokI

• Alters the first ATG start site to ACG
• Begin translation three codons downstream
• VDR is three amino acids shorter (424 aas vs 427 aas)
• Correlated with reduced bone density
• Functional importance [22]
• Suspected to alter the activity of the VDR protein
• Modulate susceptibility to type 2 diabetes [31]
• SelfDecode test
• G codes for a 424 aminoacid protein
• A allele codes for a 427 aminoacid protein
• Different ability to induce vitamin D-dependent genes [29]

Minor Allele: A = 33%

• Lower VDR activation
• Lower levels of VDR
• AA= higher bone mass and better bone structure
• Presence of the A allele results in
• Production of a VDR protein that is less effective as a transcriptional activator
• VDR protein can't induce its target genes as well.
• 1.26X increased risk of developing breast cancer
• AA= 34% higher breast cancer risk in the Nurses' Health Study
• Smaller studies of this snp and breast cancer risk were null
• Increased risk of kidney stones in Asians (one or two As)
• AA had worse survival odds for oral cancers
• Presence of the A allele
• VDR protein that is less effective as a transcriptional activator [29]
• Can't induce its target genes as well.
• A had higher risk of oral lichen planus [29]

Major Allele: G = 67%

• Higher risk of oral lichen planus
• G allele results in a protein with a different size
• Only known protein changing SNP in VDR gene [29]
• GG= Increased risk of aggressive gum disease in Chinese and Korean populations [29]
• 2-fold increase in risk of developing discopathies (such as herniated disc) and/or osteochondrosis (derangement of bone growth)
• A allele was protective [29]

RS2238136 (VDR) CC

• SelfDecode test
• 4817 G>A (rs2238136)
• Probable risk factor for colorectal cancer [PMID 22167329]
• Variation in the vitamin D receptor gene is not associated with risk of colorectal cancer in the Czech Republic [PMID 20585998]
• Lack of Associations between Vitamin D Metabolism-Related Gene Variants and Risk of Colorectal Cancer [PMID 24568525]
• Importance: 1

Minor Allele: T = 17%

Major Allele: C = 83%

RS2239182 (VDR) CC

• SelfDecode test
• [PMID 24120391] Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population
• [PMID 15651992] Variants in the vitamin D receptor gene and asthma.
• [PMID 19454612] Vitamin D pathway gene variants and prostate cancer risk.
• [PMID 19956101] Overview of the Rapid Response data.
• [PMID 21357399] Vitamin D receptor (VDR) and group-specific component (GC, vitamin D-binding protein) polymorphisms in myopia.
• [PMID 26521212] Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: A population-based study

RS2239185 (VDR) AA

• SelfDecode test
• [PMID 15651992] Variants in the vitamin D receptor gene and asthma.
• [PMID 16600026] Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway.
• [PMID 18593774] Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans.
• [PMID 18936436] Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.
• [PMID 19622139] Association study between vitamin D receptor gene polymorphisms and asthma in the Chinese Han population: a case-control study.
• [PMID 19745160] Trend tests for genetic association using population-based cross-sectional complex survey data.
• [PMID 19753122] Analysis of SNPs and haplotypes in vitamin D pathway genes and renal cancer risk.
• [PMID 20006704] Lead and cognitive function in VDR genotypes in the third National Health and Nutrition Examination Survey.
• [PMID 25750310] Vitamin D Receptor Genetic Polymorphisms Are Associated with PSA Level, Gleason Score and Prostate Cancer Risk in African-American Men
• Importance: 1

Minor Allele: G = 50%

Major Allele: A = 50%

RS2239186 (VDR) AA

• SelfDecode test
• [PMID 22480149] Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women
• [PMID 22544453] Early life sun exposure, vitamin D-related gene variants, and risk of non-Hodgkin lymphoma
• [PMID 15651992] Variants in the vitamin D receptor gene and asthma.
• [PMID 16600026] Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway.
• [PMID 19956101] Overview of the Rapid Response data.
• [PMID 19956103] Association analyses of the vitamin D receptor gene in 1654 families with type I diabetes.
• [PMID 25799011] Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk

RS3782905 (VDR) CG

• SelfDecode test
• [PMID 15651992] Variants in the vitamin D receptor gene and asthma.
• [PMID 16600026] Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway.
• [PMID 18593774] Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans.
• [PMID 19454612] Vitamin D pathway gene variants and prostate cancer risk.
• [PMID 19622139] Association study between vitamin D receptor gene polymorphisms and asthma in the Chinese Han population: a case-control study.
• [PMID 19956101] Overview of the Rapid Response data.
• [PMID 20687218] Vitamin D pathway gene variants and prostate cancer prognosis.
• [PMID 21048058] Vitamin D receptor gene polymorphisms are associated with adiposity phenotypes.
• [PMID 25750310] Vitamin D Receptor Genetic Polymorphisms Are Associated with PSA Level, Gleason Score and Prostate Cancer Risk in African-American Men
• [PMID 26521212] Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: A population-based study

RS3819545 (VDR) AA

• SelfDecode test

RS4516035 (VDR) TT

• SelfDecode test
• Importance: 1

Major Allele: T = 82%

Minor Allele: C = 18%

• 117 healthy European peri- and postmenarcheal girls (14.9 +/- 1.6 years) were followed for 4 years along with their calcium intake
• Rs4516035(C;T) and (C;C) genotypes had 13% lower spine mineral content
• If their milk intakes were below 260 mL/day
• Compared to either genotype-matched girls with higher milk intakes or to girls with the (T;T) genotype
• Rs4516035(C;T) and (C;C) female teens need more milk than rs4516035(T;T) girls to have optimal bone density
• [PMID 19105801] rs4516035 and the more aggressive tumour location in head-neck and trunk (OR=1.54, p=0.020)
• [PMID 18587672] Vitamin D receptor variants and breast cancer risk in the Polish population
• [PMID 20046590] The unfavorable effect of the A allele of the vitamin D receptor promoter polymorphism A-1012G has different mechanisms related to susceptibility and outcome of malignant melanoma
• [PMID 20394945] Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment
• [PMID 21365644] Vitamin D receptor polymorphisms in patients with cutaneous melanoma
• [PMID 22544453] Early life sun exposure, vitamin D-related gene variants, and risk of non-Hodgkin lymphoma
• [PMID 17130574] Protection from type 1 diabetes by vitamin D receptor haplotypes.
• [PMID 18205531] Vitamin D receptor gene haplotypes and susceptibility to HIV-1 infection in injection drug users.
• [PMID 19309297] Higher milk requirements for bone mineral accrual in adolescent girls bearing specific caucasian genotypes in the VDR promoter.
• [PMID 19450131] Application of pharmacogenomics to vaccines.
• [PMID 19615888] Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case-control comparisons and a meta-analysis of published VDR data.
• [PMID 19679055] Vitamin D receptor variants and the malignant melanoma risk: a population-based study.
• [PMID 19682379] TagSNP transferability and relative loss of variability prediction from HapMap to an admixed population.
• [PMID 20015871] Pharmacogenetic risk factors for altered bone mineral density and body composition in pediatric acute lymphoblastic leukemia.
• [PMID 20398755] Growth, calcium status and vitamin D receptor (VDR) promoter genotype in European children with normal or low calcium intake.
• [PMID 20716226] Clinical and genetic predictors of response to narrowband ultraviolet B for the treatment of chronic plaque psoriasis.
• [PMID 26303648] Association of vdr, cyp27b1, cyp24a1 and mthfr gene polymorphisms with oral lichen planus risk

RS7041 (VDR) AC

• SelfDecode test

RS731236 (VDR) AG - VDR Taq I

• VDR polymorphism in exon 9
• Suspected to alter the activity of the VDR protein
• Modulate susceptibility to type 2 diabetes [31]
• Significantly associated with type 2 diabetes among Caucasian Americans from European origin
• Including dyslipidemia, hypertriglyceridemia, and low HDL levels were correlated with the reported VDR polymorphism
• In concordance with another research conducted in Saudi Arabia
• Other researchers failed to demonstrate a similar link among Indians, Turkish and Polish Populations
• Differences in population genetics [31]
• SelfDecode test
• Importance: 4

Major Allele: A = 72%

• AA= Increased VDR levels in stimulated immune cells.
• AA had a 31% lower risk of Parkinson's (p=0.04) [29]
• AA confers protection against Multiple Sclerosis in HLA-DRB1*15-positive individuals [29]
• AA= Increased risk of kidney stones in Asians [29]
• Women with AA who consumed more than the median level of calcium had lower breast cancer rates [29]
• Possible increased muscle strength in school children [29]
• AA genotype is associated with increased VDR expression
• In MBP-stimulated PBMC from patients
• AA confers protection against MS in HLA-DRB1*15-positive individuals

Minor Allele: G = 28%

• GG= Increased risk of gum disease.
• Weak evidence for an association between the G allele and Multiple Sclerosis
• (T›C in exon 9...T=T, C = t)

RS757343 (VDR) CT

• SelfDecode test
• Significantly associated with polycystic ovary syndrome (PCOS) risk

Minor Allele: T = 13%

• "T" allele
• Significantly undertransmitted from parents to affected children in Type 1 diabetes (T1D) (P = 0.032, P = 0.002, respectively)
• Greater serum vitamin D
• Increased risk of prostate cancer in "T" allele carriers (P trend= 0.01)
• Associated with a 74% increased risk of severe phenotype development of polycystic ovary syndrome (PCOS) (OR, 1.74)

Major Allele: C = 87%

• "C" allele was overtransmitted

RS7975232 (VDR) AA

• SelfDecode test
• Importance: 4

Minor Allele: C = 48%

• CC= presumably results in better vitamin D receptor function.
• CC= higher bone mass and better bone structure [29]
• 37% decreased risk of Parkinson's in a population of hispanics who were exposed to more sun [29]
• Increased protection against asthma in the Chinese (one or two Cs) [29]
• 1.6 X increased susceptibility for lung cancer in smokers carrying a C [29]

Major Allele: A = 52%

• AA= Significantly increased risk of gum disease in non-smokers [29]
• AA= Increased protection from Thyroid cancer (follicular carcinoma) [29]
• An intronic C›A replacement.....A=A, C = a

Apa I

• Suspected to alter the activity of the VDR protein
• Modulate susceptibility to type 2 diabetes [31]

Bsm I

• Mut. in intron 8
• Suspected to alter the activity of the VDR protein
• Modulate susceptibility to type 2 diabetes [31]
• Significantly associated with type 2 diabetes among Caucasian Americans from European origin
• Including dyslipidemia, hypertriglyceridemia, and low HDL levels were correlated with the reported VDR polymorphism
• In concordance with another research conducted in Saudi Arabia
• Other researchers failed to demonstrate a similar link among Indians, Turkish and Polish Populations
• Differences in population genetics [31]

EcoR V

• Suspected to alter the activity of the VDR protein
• Modulate susceptibility to type 2 diabetes [31]

Hair follicle (HF) cycling

• Hair loss in animals and subjects with VDR mutations
• But not in animals and subjects with mutations in CYP27B1
• Enzyme producing 1,25(OH)2D [22]
• Vitamin D Receptor can have effects without Calcitriol to increase hair growth (via Wnt) [29]
• Alopecia well described characteristic of mice and humans lacking VDR
• Failure to regenerate the cycling lower portion of the HF after the initial developmental cycle is completed [24]
• Deletion of CYP27B1 and CaSR
• Do not result in alopecia
• VDR null mice
• Loss of HF cycling
• Gradual loss of the proliferative potential in the stem cells of the HF bulge region
• Failure of the progeny of these stem cells to migrate out of the bulge rather than their loss of proliferative potential [24]