Vitamin D Receptor / DRAFT
WORK IN PROGRESS
Regulation of VDR
Human cytomegalovirus induces Vitamin D resistance
Vitamin-D supplementation is considered to play a beneficial role against multiple viruses due to its immune-regulating and direct antimicrobial effects. In contrast, the human cytomegalovirus (HCMV) has shown to be resistant to treatment with vitamin D in vitro by downregulation of the vitamin-D receptor. (R6)
Impairment from low Methylation potential
Low methylation potential inactivates vitamin D signalling by disrupting interaction between VDR and PGC1a, and by increased destruction of VDR due to over-expression of HSP90:
Of interest, under MDD (methyl donor deficiency), the bone development effects of 1,25-dihydroxyvitamin D3 were ineffectual and these could be rescued by the addition of S-adenosylmethionine, which restored expression of arginine methyltransferase 1, PGC1a, adiponectin, and HSP90. In conclusion, MDD inactivates vitamin D signaling via both disruption of VDR–PGC1a interaction and sequestration of nuclear VDR attributable to HSP90 overexpression. These data suggest that vitamin D treatment may be ineffective under MDD. (R8)
Common polymorphisms
Several single nucleotide polymorphisms (SNPs) have been identified in the VDR gene including Taq-I, Bsm-I, and Apa-I polymorphisms, which are located at the 3′ untranslated region (3′ UTR) of the gene and are suspected to alter VDR expression. While another polymorphism known with Fok-I restriction site is located within the 5′ end near the promoter region. Fok-I is a functional polymorphism that results in different translation initiation sites on VDR that lead to three amino acids becoming longer and less effective protein. (R2)
Taq-I
(T>C) @ rs731236.
Fok-I
SNP rs2228570 (aka rs10735810):
- missense c.2T>C: M1T, M51T; source. Likely benign. Shorter version, more active protein.
- missense c.2T>G: M1R. Likely Pathogenic. source.
- missense c.2T>A: M1K. Likely Pathogenic. source
This SNP is also known as the Fok-I polymorphism due to the presence or absence of a restriction enzyme site. It is a coding non-synonymous SNP in the translational initiation codon that determines the formation of two protein variants: a longer version of the VDR protein that corresponds to the T allele and a form shortened by three amino acids corresponding to the C allele. Several in vitro studies showed that the shortened VDR form was more effective in transactivation of the vitamin D signal. (R5)
From the genetic perspective, it is important to note that the Fok-I RFLP can be considered an independent marker in the VDR gene since there is no LD with any of the other VDR polymorphisms and the LD area surrounding this polymorphism seems to be very small. Therefore, LD with another polymorphism is not a likely explanation for the associations. (R3)
In conclusion, we can state that the Fok-I polymorphism seems to be functional and that the 424 aa VDR variant is somewhat more active than the 427 aa variant in terms of its transactivation capacity as a transcription factor. There might be a gene-specific effect in that some promoter areas of vitamin D target genes might be more sensitive to thisVDR genotype-dependent difference in activity, while others may not. (R3)
the polymorphism Fok-I (rs10735810) near the 5′ end of the VDRG. The Fok-I polymorphism leads to a 3 amino-acids longer VDR protein by directly introducing a start codon. A functional impact of this polymorphism on the immune response has been demonstrated. (R4)
Apa-I
rs7975232
Bsm-I
rs1544410
Cdx2
The Cdx2 polymorphism has been well characterized by the studies of Arai et al. (2001) and Yamamoto et al.(1999). The G to A polymorphism is located in a Cdx2 binding site in the 1e promoter region, and this site is suggested to play an important role in intestinal-specific transcription of the VDR gene. As the intestine is the predominant area for calcium absorption, the Cdx2 site is thought to influence the vitamin D regulation of calcium absorption. The A allele has been demonstrated to be more‘‘active’’ than the G-allele by binding the Cdx2 transcription factor more strongly and by having more transcriptional activity (Arai et al., 2001). Thus, the A allele is thought to cause increased VDR expression in the intestine and, thereby, can increase the transcription of calcium transport proteins (such as calbindin 9K and 28K,TRPV5, TRPV6). This could thereby enhance the intestinal absorption of calcium and, thereby, to result in in-creased BMD. Although this increased BMD has indeed been demonstrated for Japanese women who carry the A allele (Arai et al., 2001), this was not found in Caucasian women(Fang et al., 2003). Yet, the A allele of this polymorphism was indeed found to be associated with decreased fracture risk (as would be expected from having an increased BMD) in a large study of Caucasian women, but independently of BMD. (R3)