Wednesday, March 23, 2016

Complex Science: The Role of Vitamin D Receptor (VDR) Genotype Polymorphisms (SNPs)

Vitamin D regulates the expression of hundreds of genes, with widespread hormonal and immune effects.  But whether vitamin D is good for you may depend on your genes.  According to one hypothesis, supplemental vitamin D causes allergies and asthma.  [1]

But the biochemistry is complex.  The main circulating metabolite is 25-hydroxyvitamin D or 25(OH)D, a biomarker of vitamin D status.  The active vitamin D metabolite 1,25(OH)2D3 binds to nuclear vitamin D receptor (VDR), which exists from under 500 to over 25,000 copies per cell in many human tissues including thymus, bone marrow, B and T cells and lung alveolar cells.  Gene expression can be varied over a 100-fold range by subtle modifications of introns and promoter regions outside of the gene[1]

The SNPs that seem to affect VDR are not in the exon; they may affect RNA production in the promoter region. It is unlikely that increased or decreased vitamin D sensitivity is simply mediated by a genetic variation in the VDR. Vitamin D requires several enzymatic steps to be activated, transported and degraded; receptor signalling requires several co-factors and all of these may contribute additive or multiplicative effects on vitamin D sensitivity.

Possibly because of this complexity, progress in this field has been slow.  I reviewed several papers, most of which found very small or no effects from common SNPs.  For example, although most papers found insufficient or deficient levels of vitamin D throughout the population, a case-control study only found a small effect on circulating 25(OH)D from one of the SNPs tested. [2].  A randomized controlled trial found effects from more SNPs, but each contributed very small effect sizes. All SNPs tested had, at most, +/-5% effect on circulating 25(OH)D. : "Three SNPs had statistically significant interactions: rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR, with per allele effect sizes ranging from −4% to +3% differences in [25(OH)]."[3]

These complex and unimpressive results are representative of the difficulties inherent in assaying SNPs for clinically-relevant phenotypes.  Most SNPs slightly modify expression or binding of a protein, such that it takes the combination of dozens or hundreds of different SNPs to create any significant phenotype.  Biochemistry is complex, and it is always possible that other gene or protein interactions can ameliorate or exacerbate any small perturbation from any given SNP.

[1] Variants in the vitamin D receptor gene and asthma.  2005.  

[2] Vitamin D levels and vitamin D receptor gene polymorphisms in asthmatic children: a case–control study.

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