Tu1821 The Gene Encoding the Human Organic Anion Transporting Polypeptide Oatp1a2 (Gene Symbol Slco1a2) is Transactivated by the Vitamin D Receptor (VDR)

Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor.

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Effect of SLCO1B1 gene polymorphisms and vitamin D on statin-induced myopathy

Drug Metabolism and Personalized Therapy ◽

10.1515/dmpt-2017-0030 ◽

2018 ◽

Vol 33 (1) ◽

pp. 41-47 ◽

Cited By ~ 5

Author(s):

Baraa Alghalyini ◽

Said El Shamieh ◽

Ali Salami ◽

Sophie Visvikis Siest ◽

Hana M. Fakhoury ◽

...

Keyword(s):

Vitamin D ◽

Organic Anion ◽

Substantial Reduction ◽

Cardiovascular Complications ◽

Organic Anion Transporter ◽

Gene Encoding ◽

Transporter Protein ◽

Cholesterol Levels ◽

Hybridization Probes ◽

Anion Transporter

Abstract Background Statin therapy used to lower cholesterol levels results in a substantial reduction in cardiovascular complications. Previous observations in different ethnic populations showed that rs2306283A>G, p.Asn130Asp and rs4149056T>C, p.Val174Ala in solute carrier organic anion transporter 1B1 (SLCO1B1) gene encoding the organic transporter protein may be responsible for statin uptake, thus explaining the majority of statin-associated symptoms. In addition to the genetic component, vitamin D (vit D) deficiency is common in Saudi Arabia and worldwide and may cause muscle dysfunction and ache. The aim of the present study was first to reveal an effect of vit D, rs2306283A>G, and rs4149056T>C and related haplotypes on statin-associated myopathy (SAM) and then to investigate a possible interaction between low vit D levels and the above-mentioned variants. Methods The genomic DNA obtained from 50 individuals diagnosed with hypercholesterolemia was genotyped using light SNiP hybridization probes. Results Low vit D levels were associated with SAM (OR=3.6, p=0.03); however, CK levels, rs2306283A>G, and rs4149056T>C did not show any association. Interestingly, rs4149056T>C was interacting with vit D to influence SAM (p=0.02). Haplotype analysis showed that SLCO1B1 *1B and *15 were more prevalent in individuals with SAM (p=0.05). When stratified according to vit D levels, rs2306283A allele showed an increase in individuals having SAM along with low vit D (p=0.03). Conclusions Although preliminary, our results show an involvement of vit D and rs4149056T>C of SLCO1B1 in SAM.

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