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How Genetic Variants Impair Vitamin D Production

By Dr. Emily Brown Reeves, PhD, CNS

The prohormone 25-hydroxyvitamin D (calcidiol), which is measured in serum, is the standard clinical measurement for vitamin D status.  25-hydroxyvitamin D is used to assess vitamin D status because it is a stable metabolite with a half-life of 15 days. The active form of vitamin D, 1,25-hydroxyvitamin D, also known as calcitriol, is not used because it is primarily controlled by parathyroid hormone levels and has a very short half life.  Serum levels of 25-hydroxyvitamin D below 20 ng/mL are considered deficiency and a level between 21 ng/mL and 29 ng/mL is considered an insufficient level of Vitamin D.(4) An optimal level of 25-hydroxyvitamin D has not been established, however,  levels between 54-90 ng/mL are the serum level ranges for sun exposed individuals.(3) Levels above 250 ng/mL are considered toxic and are usually associated with symptoms such as lethargy, kidney injury, nausea, and dehydration.  Levels greater than 60 ng/mL have been associated with hypercalcemia, the development of kidney stones, weak bones, and impaired brain health.(5) Importantly, photolytically derived Vitamin D has never been reported to cause toxicity. Therefore, when blood levels are at or near 60 ng/mL, there should be no further supplementation, although sun exposure does not need to be restricted.

The Vitamin D Synthesis Pathway

Circulating levels of calcidiol and calcitriol are not only affected by sun exposure and vitamin D intake but also by genetic predisposition and metabolism. In the following paragraph, the biochemical pathway for converting vitamin D will be outlined and then in subsequent sections how genetic variation might influence the pathway’s production will be discussed.

UVB radiation photolytically converts 7-dehydrocholesterol (7-DHC) to vitamin D3 (cholecalciferol) in the stratum spinosum and stratum basale layers of the skin.(2)  Vitamin D3 is then converted to calcidiol in the liver mitochondria and endoplasmic reticulum by CYP2R1 and CYP27A1 respectively.(6)  CYP27A1 cannot convert vitamin D2 (ergocalciferol) to calcidiol, but CYP2R1 converts both D3 and D2 with similar affinity.(6)  CYP2R1 is the major contributor to levels of calcidiol with CYP27A1 playing a more minor role.  Both are important but not the sole contributors as a deletion of both in mice do not cause calcidiol levels to drop to zero.(15)  Biological redundancy is advantageous but it complicates the practice of nutritional genomics. To give an example:  Deletion of CYP2R1 (the major enzyme for vitamin D) in mice results in only a 50% loss of calcidiol.(15)  If the human system is analogous to the mouse system, then a loss-of-function mutation in CYP2R1 would cause only a 50% reduction of the levels of calcidiol. Calcidiol is activated to the hormone calcitriol in the kidneys by the enzyme CYP27B1.(6)  Unlike calcidiol, which can be formed by several 25-hydroxylases, calcitriol is only known to be formed by CYP27B1.(6)  Correspondingly, loss-of-function mutations in CYP27B1 have been linked to vitamin D dependent rickets.(9)  Intracellular levels of active vitamin D hormone are maintained by the tight regulation of CYP27B1 by parathyroid hormone PTH, calcitriol, and fibroblast growth factor 23 (FGF23).(6)  When calcium is low, CYP27B1 is upregulated by high PTH levels.(6)  High phosphate levels downregulate CYP27B1 through FGF23 and high levels of calcitriol downregulate the enzyme by preventing transcription of CYP27B1.(6) Genetic alterations in CYP27B1 or other components of this regulatory system may affect the circulating levels of calcitriol as well as the system’s ability to detect low calcium levels and restore them.  The active form of Vitamin D is broken down to biologically inactive calcitroic acid by CYP24A1, a 24-hydroxylase.(6)  Deletion of CYP24A1 in mice results in improper formation of the intramembranous bone due to a buildup of calcitriol.(10) Mutations in this enzyme may result in toxicity due to inability to inactivate the hormone vitamin D.

Management of Vitamin D levels by the Body

Calcium levels are maintained in the body within a narrow range 8.5-10.5 mg/dL to ensure proper neural signaling.(7) Both low and high extracellular calcium are associated with disease.(7) Hypocalcemia is associated with the severe side effects of tetany, seizures, psychosis and cardiovascular effects.(7) Hypercalcemia may produce nausea, anorexia, accumulation of calcium in soft tissue, and electrocardiograph disturbances.(7) Abnormal calcium levels in the brain are also implicated in Alzheimer’s disease.(8) Vitamin D maintains a narrow range of extracellular calcium by interaction with the vitamin D receptor (VDR) and other genes to control expression of calcium homeostasis genes.(6) These mechanisms allow vitamin D to 1.) potentiate the action of parathyroid hormone (PTH) on bone to release calcium 2.) increase calcium and phosphorus uptake from the digestive tract and 3.) increase the resorption of calcium from the kidney tubules.(7)

When considering genetic variation that may affect vitamin D’s maintenance of calcium, vitamin D’s cooperation with parathyroid hormone (PTH) should not be overlooked.  In the absence of sufficient dietary calcium intake and detection of low ionized calcium in the blood, PTH is released.(7)  PTH causes the extracellular bone matrix to release calcium into the blood to restore levels.(7)  This process is dependent upon calcitriol.(7)  PTH does not cause increased calcium as a result of more osteoclast activity or bone turnover unless the calcium deficiency is prolonged.(7) PTH also increases the tubular resorption of calcium and magnesium. Genetic variation resulting in impairment of the PTH response will also affect vitamin D’s control of calcium homeostasis but is beyond the scope of this discussion.

Vitamin D’s role in regulation of gene transcription

Active vitamin D can exert genomic and nongenomic actions.  Genomic actions are mediated by calcitriol binding to the vitamin D receptor (VDR) which is expressed in nearly every tissue.(11)  Binding of active vitamin D causes VDR to heterodimerize and interact with the retinoid X receptor (RXR).(12)  This complex recruits other coactivator proteins and controls transcription at DNA sites called vitamin D response elements (VDREs).(12) There are thousands of VDREs regulating a diversity of genes many of which are not involved with calcium homeostasis.(12)  vitamin D’s other biological functions are just beginning to be appreciated.  For example calcitriol’s interactions with VDR have recently been shown to directly stimulate the production of testosterone, estradiol, estrone and progesterone.(13) Further investigation of this mechanism may help to link the observation that infertility is associated with low vitamin D levels.(14)  As knowledge increases about VDRE’s it is anticipated that some SNPs will be identified that ameliorate control at a VDRE by preventing binding of the vitamin D-VDR-RXR complex.  Practitioners working in nutritional genomics should be aware of this category of SNPs and anticipate future discussions regarding their effects.

The nature of the variants to be discussed

I will now turn to discuss genetic variants affecting vitamin D homeostasis. In the field of genomics, disease-causing variants are assigned a scientific validity score of being “pathogenic”, “likely pathogenic”, “uncertain significance”, “likely benign”, or “benign” according to the guidelines established by the American College of Medical Genetics. Future research may move SNPs from the categories of “uncertain significance” and “likely benign” either to “benign” or “likely pathogenic”. Please note that the variants I will discuss do not usually fall into the “pathogenic” or “likely pathogenic” categories as they often have much more mild effects upon an individual and occur at a >1% frequency in the population. Practitioners should recognize that variants classified as “likely benign” or “benign” accordingly to ACMG criteria while not causing full-blown disease may still impact an individuals risk for vitamin D deficiency. For example, any mutation in CYP27B1 that impairs the enzymatic activity will predispose an individual to vitamin D deficiency because CYP27B1 is the sole enzyme responsible for this step. But, many variants in CYP27B1 lack sufficient study precluding their precise effects on vitamin D levels being known and therefore intervention information is not available. Practitioners can always find the most up-to-date information about a genetic variant by checking recent publications for a given variant in the databases of dbSNP, ClinVar, Varsome, and the human genome browser.

Genetic variants that affect Vitamin D levels

CYP2R1

CYP2R1 is now recognized as the major enzyme converting the preprohormone to calcidiol.(16) CYP2R1 is found in the endoplasmic reticulum of the liver and when deleted in mice causes a 50% decrease in calcidiol.(15) The importance of CYP2R1 in human homeostasis and metabolism of vitamin D is evidenced by the observation of two missense mutations in CYP2R1 (L99P & K242N) causing vitamin D dependent rickets type 1B in the Nigerian ethnicity.(17) A mutation in CYP2R1 that is a risk factor for vitamin D deficiency is rs10741657.(18) It is associated with at least 70 publications and has been linked to an increased risk of developing Type I diabetes(18,19) and coronary artery disease.(20) There is direct evidence for this variant to lower the calcidiol level.(21) Importantly, it has been shown that homo- and heterozygotes for rs10741657 had normalized calcidiol levels after supplementation with 40,000 IU vitamin D/week for 6 months.(21) People carrying this variant should be advised to have their vitamin D levels checked annually and ensure adequate sun exposure.

VDR

The vitamin D receptor (VDR) gene has an autosomal recessive gene-disease association with vitamin D dependent rickets type 2A. Here we will discuss VDR variants that appear at >1% frequency in the population, which means they won’t cause full-blown disease, but may still affect an individual’s predisposition to vitamin D deficiency or excess.

A variation in the promoter region of VDR known as Cdx2 (rs11568820) reduces the transcription of VDR by 70%.(22) This SNP is thought to specifically impair intestinal expression of VDR.(23)  Since the intestine is where calcium is absorbed, this variation may prevent vitamin D  from assisting with calcium absorption. There is some mechanistic information and multiple studies linking this variant to fracture risk and bone mineral density (BMD).(22,24) Future hypotheses to be tested include whether an individual homozygous for rs11568820 might have a higher optimal vitamin D level in contrast to someone without this variation.

Another common SNP to discuss is rs2228570, commonly called FokI. This SNP causes the VDR protein to have stronger transcriptional activity by eliminating the start site of exon 2 and shortening VDR by three amino acids.(11) As expected for a VDR with stronger transcriptional activity, adults with this variant have been shown to have higher calcium absorption than individuals without.(25) Lastly, for postmenopausal women with the variant, they were more responsive to calcium and vitamin D repletion.(26) This variant has a lot of mechanistic insight and multiple studies linking it to disease.

Variants near to the 3’ end of the VDR gene include VDR-BsmI, VDR-ApaI, and VDR-TaqI.(23) The 3’ untranslated region (UTR) of a gene can control the expression of that gene by determining the stability of the mRNA transcript.(23) The VDR gene has many polymorphisms in the three prime untranslated region (3’UTR) and there is strong linkage disequilibrium between this region and the markers BsmL, ApaI, and TaqI. Linkage disequilibrium is the more likely explanation for the associations between these markers and effects on the expression of the VDR than the alternative possibility that BsmL, ApaI, and TaqI are the functional sequence variations.(23) The major haplotypes for this region are BsmL-ApaI-TaqI “BAt” or “baT”.(23) An individual homozygous for the first haplotype would be BAt-BAt and homozygous for the second haplotype would called baT-baT.  The “baT” haplotype is the more stable transcript which should theoretically result in greater VDR expression, though this has not been observed.(23)  Although the transcript levels are higher for baT, the VDR expression is lower.(23) This picture is quite complicated and remains poorly understood with multiple conflicting studies.(23) Many of the conflicting reports are likely due to usage of these markers (BsmL, ApaI, and TaqI) instead of the functional variation. Usage of different cell types and culture conditions has also contributed to conflicting results.(23)

BsmL is rs1544410 C>T and for the “BAt” notation “B” corresponds to “G” or “C” depending on the strand while the “b” of “baT” corresponds to “T” or “A” depending on the strand.  BsmL has been associated with a decreased response to treatment for osteoporosis in postmenopausal women.(27) Another study for the effects of long term treatment of epilepsy on bone density noted that the CC genotype was associated with a higher BMD and calcidiol but lower level of parathyroid hormone.(28) There is not clear mechanistic information and conflicting studies for this variant. Similarly ApaI and TaqI must also be classified as “not demonstrated” because of a lack of clear mechanistic information. However, ApaI and TaqI have studies showing linkage to disease. For ApaI there is a study linking one copy of the A allele and dairy consumption to a decreased risk of colorectal cancer recurrence.(29) The TaqI polymorphism has also been associated with fracture risk and recently shown to increase the severity of Type I Diabetes.(30,31) Although, overall it can be argued that the haplotype “BAt” produces a higher expression level of VDR, more research is needed to fill in the current gaps of understanding.(23)

GC or VBP

Between 80-90% of circulating calcidiol and calcitriol is bound to group specific component of serum (GC) now renamed vitamin D binding protein (VBP).(32)  VBP may protect the prohormone and hormone from degradation as well as control delivery to tissues.(32)

The variant rs2282679 causes the largest decrease in serum calcidiol out of all the variants in VBP identified by GWAS.(21)  In spite of lowering the concentration of calcidiol, rs2282679 has minimal influence on coronary artery disease, body mass index (BMI), and colorectal cancer.(21,33,34,35) Also there is no demonstration of association with fracture risk. So although rs2282679 has direct evidence for lowering serum calcidiol, it has not been linked to disease.

The variant rs7041 does not correlate with calcidiol levels but is associated with the severity of chronic periodontitis in the Iranian population along with risk for PCOS in Indian women deficient in vitamin D.(33,36) There are several studies linking this variant to disease but no clear dietary advice and insufficient knowledge of mechanism.

Another variant in VBP is rs4588 which is very near to rs7041 (11 bp away).  rs4588 is also in linkage disequilibrium with rs2282679 but about 1000 bp away.  rs4588 has been associated with at 3.5 ng/mL decrease in calcidiol per copy of the allele.(37) rs4588 has also been associated with an increased risk for metabolic syndrome.(37,38)  This variant has two disease linkage studies and is known to lower serum vitamin D.

In clinical practice for clients with these variants in VBP, it is important to monitor levels of vitamin D and ensure adequate sun exposure. However, since the role of VBP remains unclear and there is no evidence about repletion, no specific advice can be given at this time for intervention. For example the hormone binding hypothesis says that bound hormones are not accessible to tissue.  If this is the case with VBP, then genetic alterations may cause differences in the bioavailable vitamin D. Therefore, lower serum levels of vitamin D could actually be a compensatory mechanism to lower bioavailable vitamin D hormone to a nontoxic amount. 

CYP27B1

Pathogenic or likely pathogenic mutations in CYP27B1 are responsible for the autosomal recessively inherited disease Vitamin D Dependent Rickets Type I (VDDR I).(9)  Mutations which result in partial impairment of this enzyme cause people to be at a higher risk for vitamin D deficiency.  The clinical presentation of impairment in CYP27B1 will be elevated or normal levels of calcidiol with low levels of the active hormone.  Therapy should involve treatment with calcitriol and monitoring of calcidiol, calcitriol, and parathyroid hormone.

The variant, rs4646536, has been associated with Type I diabetes(39), islet autoimmunity in Type I diabetes(39,40), susceptibility and prognosis of childhood asthma(41), reduced risk for colorectal cancer(42), improvement of the immune response to tuberculosis with vitamin D repletion and improved outcomes for esophageal squamous cell carcinoma following supplementation of vitamin D3.(43,44) Consistent with CYP27B1’s place in the vitamin D pathway, this variant is not associated with differences in the calcidiol level as it is downstream in the pathway. This variant has multiple studies for disease connections, the biological mechanism involving CYP27B1 is fairly well understood and there are studies showing benefits of supplementation of vitamin D3.

The second variant in CYP27B1 relevant for nutritional genomics is rs10877012 which is associated with autoimmune endocrine disorders, asthma risk, and Type I diabetes.(45,46)  This variant is in perfect linkage disequilibrium with rs4646536.  This variant has been proposed to reduce the expression of CYP27B1.  Therefore, it has been hypothesized that the association between this variant and the increased risk for Type I diabetes may be due to insufficient calcitriol levels.  Alternatively, CYP27B1 may be inadequately expressed in important immune regulatory cells.  This variant has also been shown to result in increased fracture risk in the elderly.(47) Accordingly this varinat has numerous studies for disease connections and the biological mechanism involving CYP27B1 is fairly well understood.

References

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