Oct 14, 2023
Vitamin D affects calcium and phosphate levels in our body and is responsible for bone health. Vitamin D deficiency; It has been linked to diseases such as cancer, autoimmune disease, Type 1-2 Diabetes, bone disease, heart disease and hypertension. Some studies have shown that vitamin D levels are hereditary. It has been observed that vitamin D levels are associated with GC, CYP2R1 and VDR genes (Dastani, Z., et. al., 2013).
Dietary sources of vitamin D; cod liver, fatty fish, eggs and fortified milk. In addition to nutritional sources, our body synthesizes vitamin D through the sun. There are 2 forms of vitamin D; D2-ergocalciferol of plant origin; D3-cholecalciferol of animal origin (Haddad JG, et. al., 1993).
Vitamin D and VDR Gene Relationship
Most of vitamin D activity is mediated by a nuclear transcription factor known as VDR (vitamin D receptor). 1,25 dihydroxyvitamin D enters the cell nucleus and combines with VDR, and another nuclear receptor called retinoic acid X receptor (RXR) strengthens this association. In the presence of 1,25 dihydroxyvitamin D, the VDR/RXR complex initiates molecular interaction reactions that will modulate the transcription of many specific genes (Acarkan, T., 2015). VDR gene polymorphisms have been associated with an increased risk of various autoimmune and inflammatory diseases, such as type 1 diabetes (T1D), multiple sclerosis (MS), and asthma. There are four commonly studied VDR polymorphism sites (BsmI, Apal, Foki and TaqI). The BsmI and ApaI polymorphisms are located near the 3' end of the VDR gene in the intron between exons 8 and 9, and TaqI is located in exon 9. These polymorphisms result in silent codon mutations associated with high VDR mRNA stability, whereas the FokI polymorphism is located in exon 2 and leads to the production of a protein of different sizes (Bagheri-Hosseinabadi Z. et al., 2020).
Vitamin D and CYP2R1 Gene Relationship
Vitamin D undergoes biotransformation twice in order to be used by our body. The enzyme that provides the first conversion is hepatic enzyme 25 hydroxylase (CYP2R1). It converts vitamin D into 25-hydroxyvitamin D(25[OH]D), its main circulating form (Haddad JG, et. al., 1993). The gene for this enzyme is CYP2R1. Variations in this gene have been shown to be associated with plasma vitamin D levels (Zhang Y, et. Al., 2012).
Vitamin D and GC Gene Relationship
25(OH)D is transported in the circulation mainly bound to a specific vitamin D binding protein called GC group component (GC) (Foucan, L., et. al., 2013). Variants in this gene affect vitamin D levels (Wang, T. J., et. al. 2010).
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VITAMIN D |
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Genes |
rs |
Minor Allel |
Minor Allel Description |
Reference |
|
VDR (VDR-Bsml) |
rs1544410 |
A |
High relative risk for low vitamin D levels. |
|
|
CYP2R1 |
rs1562902 |
T |
High relative risk for low vitamin D levels. |
|
|
CYP2R1 |
rs2060793 |
A |
High relative risk for low vitamin D levels. |
|
|
VDR(VDR-Fokl) |
rs2228570 |
G |
High relative risk for low vitamin D levels. |
|
|
GC |
rs2282679 |
A |
High relative risk for low vitamin D levels. |
|
|
GC |
rs7041 |
T |
High relative risk for low vitamin D levels. |
|
|
VDR (VDRtalql) |
rs731236 |
C |
High relative risk for low vitamin D levels. |
|
|
VDR (Apal) |
rs7975232 |
A |
High relative risk for vitamin D receptor function. |
|
When the relationship between CYP2R1 gene rs2060793 polymorphism and vitamin D level was examined, it was seen that this polymorphism was associated with serum 25(OH)D (Zhang Y, et. al. 2012).
BsmI rs1544410 polymorphism may affect the function of VDR by regulating mRNA stability and protein translation efficiency and influence the effect of vitamin D on tumor inhibition. Patients carrying the VDR BsmI rs1544410-AA genotype were shown to have a lower risk of developing non-small cell lung cancer, and in the same study, the T allele for the TaqI (rs731236) SNP in the VDR gene was found to have a higher risk of non-small cell lung cancer than the CC genotype (Pineda Lancheros , L. E. et al., 2022). There are also studies showing that the VDR BsmI rs1544410-AA genotype reduces the risk of lung cancer and that the T allele in the TaqI (rs731236) polymorphism in the VDR gene is associated with a higher risk of lung cancer compared to the CC genotype (Duan GQ. et al., 2020).
It has been shown that individuals with the T allele of the VDR (VDR-Fok1) gene rs2228570 (C>T) polymorphism have significantly lower serum vitamin D levels (Tuncel G, et. al., 2019). It has been found that the "C" allele of the VDR (VDRtalql) rs731236 polymorphism is significantly associated with an increased risk of autism, while the "G" allele of the VDR (Apal) rs7975232 polymorphism may be a protective factor against the development of autism (Yang H and Wu X., 2020). In the study examining the relationship between vitamin D receptor gene polymorphism and bone mineral density in children with ApaI rs7975232 and FokI rs2228570 polymorphisms; The presence of polymorphisms has been shown to favor higher bone mass and better bone structure (Jakubowska-Pietkiewicz E, et. al., 2012).
REFERENCES
Acarkan, T. (2015). D vitamini. Bilimsel Tamamlayıcı Tıp Regülasyon ve Nöral Terapi Dergisi, 9(3), 5-8. https://dergipark.org.tr/tr/pub/barnat/issue/42340/509522
Alathari, B. E., Cruvinel, N. T., da Silva, N. R., Chandrabose, M., Lovegrove, J. A., Horst, M. A., & Vimaleswaran, K. S. (2022). Impact of Genetic Risk Score and Dietary Protein Intake on Vitamin D Status in Young Adults from Brazil. Nutrients, 14(5), 1015. https://doi.org/10.3390/nu14051015
Bagheri-Hosseinabadi Z, Imani D, Yousefi H, Abbasifard M. Vitamin D receptor (VDR) gene polymorphism and risk of rheumatoid arthritis (RA): systematic review and meta-analysis. Clin Rheumatol. 2020 Dec;39(12):3555-3569. doi: 10.1007/s10067-020-05143-y. Epub 2020 May 22. PMID: 32445089.
Dastani, Z., Li, R. & Richards, B. Genetic Regulation of Vitamin D Levels. Calcif Tissue Int 92, 106–117 (2013). https://doi.org/10.1007/s00223-012-9660-z
Duan GQ, Zheng X, Li WK, Zhang W, Li Z, Tan W. The Association Between VDR and GC Polymorphisms and Lung Cancer Risk: A Systematic Review and Meta-Analysis. Genet Test Mol Biomarkers. 2020 May;24(5):285-295. doi: 10.1089/gtmb.2019.0187. Epub 2020 Apr 7. PMID: 32255717.
Foucan, L., Vélayoudom-Céphise, F. L., Larifla, L., Armand, C., Deloumeaux, J., Fagour, C., Plumasseau, J., Portlis, M. L., Liu, L., Bonnet, F., & Ducros, J. (2013). Polymorphisms in GC and NADSYN1 Genes are associated with vitamin D status and metabolic profile in Non-diabetic adults. BMC endocrine disorders, 13, 36. https://doi.org/10.1186/1472-6823-13-36
Haddad JG, Matsuoka LY, Hollis BW, Hu YZ, Wortsman J (1993) Human plasma transport of vitamin D after its endogenous synthesis. J Clin Invest 91:2552–2555. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC443317/
Jakubowska-Pietkiewicz E, Młynarski W, Klich I, Fendler W, Chlebna-Sokół D. Vitamin D receptor gene variability as a factor influencing bone mineral density in pediatric patients. Mol Biol Rep. 2012 May;39(5):6243-50. doi: 10.1007/s11033-012-1444-z. Epub 2012 Mar 16. PMID: 22422157. https://pubmed.ncbi.nlm.nih.gov/22422157/
Nissen J, Rasmussen LB, Ravn-Haren G, Andersen EW, Hansen B, Andersen R, Mejborn H, Madsen KH, Vogel U. Common variants in CYP2R1 and GC genes predict vitamin D concentrations in healthy Danish children and adults. PLoS One. 2014 Feb 27;9(2):e89907. doi: 10.1371/journal.pone.0089907. PMID: 24587115; PMCID: PMC3937412. https://pubmed.ncbi.nlm.nih.gov/24587115/
Pineda Lancheros, L. E., Tolosa, S. R., Gálvez Navas, J. M., Martínez, F. M., Martín, A. S., Morales, A. J., & Ramírez, C. P. (2022). Effect of Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway on Susceptibility to Non-Small-Cell Lung Cancer. Nutrients, 14(21). https://doi.org/10.3390/nu14214668
Tuncel G, Temel SG, Ergoren MC. Strong association between VDR FokI (rs2228570) gene variant and serum vitamin D levels in Turkish Cypriots. Mol Biol Rep. 2019 Jun;46(3):3349-3355. doi: 10.1007/s11033-019-04796-6. Epub 2019 Apr 12. PMID: 30977086. https://pubmed.ncbi.nlm.nih.gov/30977086/
Wang, T. J., Zhang, F., Richards, J. B., Kestenbaum, B., van Meurs, J. B., Berry, D., Kiel, D. P., Streeten, E. A., Ohlsson, C., Koller, D. L., Peltonen, L., Cooper, J. D., O'Reilly, P. F., Houston, D. K., Glazer, N. L., Vandenput, L., Peacock, M., Shi, J., Rivadeneira, F., McCarthy, M. I., … Spector, T. D. (2010). Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet (London, England), 376(9736), 180–188. https://doi.org/10.1016/S0140-6736(10)60588-0
Yang H, Wu X. The Correlation Between Vitamin D Receptor (VDR) Gene Polymorphisms and Autism: A Meta-analysis. J Mol Neurosci. 2020 Feb;70(2):260-268. doi: 10.1007/s12031-019-01464-z. Epub 2020 Jan 3. PMID: 31900887. https://pubmed.ncbi.nlm.nih.gov/31900887/
Zhang Y, Wang X, Liu Y, Qu H, Qu S, Wang W, Ren L. The GC, CYP2R1 and DHCR7 genes are associated with vitamin D levels in northeastern Han Chinese children. Swiss Med Wkly. 2012 Jul 16;142:w13636. doi: 10.4414/smw.2012.13636. PMID: 22801813. https://pubmed.ncbi.nlm.nih.gov/22801813/