CYP2R1

Protein:

Cytochrome P450 2R1

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Cytochrome P450 2R1 (CYP2R1) is an enzyme which is encoded for by the gene CYP2R1. Expressed in the liver, CYP2R1 catalyzes the conversion of vitamin D, either from the diet or generated in the skin, into calcifediol which then circulates in the blood. Calcifediol can be converted to calcitriol in the kidneys, the bioactive form of vitamin D which binds with vitamin D receptors (VDR). This binding leads to an increase in calcium uptake from the gut which is required for bone formation, muscle function and numerous other processes in the body. In medicine the amount of calcifediol present in the blood is used as a marker for whole body vitamin D status, and is often used to diagnose vitamin D deficiency 13.

There are three SNPs in CYP2R1 associated with reduced levels of circulating vitamin D T-1127C, A226-2810C and T-1559C. With T-1127C in particular being associated with poor health outcomes.

T-1127C

Science Grade
A-
Musculoskeletal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs10741657 g a 31

Risk Description

The ‘G’ allele of SNP T-1127C in the CYP2R1 gene is associated with a 4% reduction in the circulating form of vitamin D calcifediol, which may in turn lead to a reduction in the amount of the bioactive form of vitamin D calcitriol and hence calcium uptake. No mechanism accounting for this reduction in activity is currently described. At a clinical level those carrying two copies of the ‘G’ allele of T-1127C showed an 8% reduction in circulating vitamin D and were at risk of developing vitamin D deficiency. However, this was dependent on other genetic (‘C’ allele of SNP A26-796C in the GC gene) and lifestyle factors such as diet and sunlight exposure 4,5.

A lack of vitamin D is typically associated with boor bone health. In children, this can manifest as the disease rickets whereby bones are softened and weakened leading to poor development. This disease has been all but eradicated in the west due to fortification of key food groups, although some may still be at risk. Adults deficient in vitamin D are at risk of developing osteomalacia, where bones are thinned, and osteoporosis where bones become more fragile. A weak association between the ‘G’ allele of T-1127C and decreased bone strength has been observed 6.

Outside of bone health vitamin D deficiency associated with ‘G’ allele of T-1127C has been associated with several cancers including breast, colon and ovarian, as well multiple sclerosis, depression and muscle weakness 7.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin D Calcitriol

CYP2R1 is responsible for converting vitamin D, either from the diet or generated in the skin, into the circulating form calcifediol, which can in turn be converted into the bioactive form calcitriol. For those with the ‘G’ allele of T-1127C, which is associated with reduced levels of circulating vitamin D, calcifediol, supplementation with the bioactive form calcitriol may help ensure that appropriate vitamin D levels are maintained ensuring proper calcium uptake maintain bone health and ensuring normal cellular function. Additionally, given that the majority of us are vitamin D deficient anyway supplementation is to be recommended to ensure both healthy calcium uptake, and that the other cellular activates dependent on vitamin D can proceed normally 8,9.

Iron

Iron is a cofactor for CYP2R1 and is required for it to function correctly. For those with the ‘G’ allele of A226-2810C, which is associated with reduced levels of circulating vitamin D, supplementation with iron may ensure that CYP2R1 is functioning maximally, although the importance of this SNP in bone health and other cellular functions is likely minor 10.

Indirect Nutrients:*

IngredientActive IngredientEffect
Calcium

The main function of vitamin D binding to VDR is to ensure proper uptake of calcium from the gut. Whilst, calcium is not typically limited in the normal diet those pursuing a vegan, or dairy free diet may consider supplementation, especially if they carry the ‘G’ allele of T-1127C 11.

Nutritional Contraindications:*

IngredientActive IngredientEffect
Caffeine

There have been numerous observations that an increase in caffeine intake associates with poor bone health and a risk of developing osteoporosis. Caffeine is thought to promote the excretion of calcium in urine, whilst simultaneously preventing the production of new bone. Whilst there is an association with increased caffeine intake and poor bone health nothing specific has been described for those carrying the ‘G’ allele of T-1127C 12.

Discuss this information with your doctor before taking any course of action.

A226-2810C

Science Grade
B-
Musculoskeletal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs10500804 t g 35

Risk Description

Two copies of the ‘G’ allele of SNP A226-2810C in the CYP2R1 gene are associated with a 10% reduction in the circulating form of vitamin D calcifediol. In those carrying a single copy of the ‘G’ allele levels of circulating calcifediol are reduced by 3%. Although this reduction in circulating vitamin D may be sufficient to lead to the development of vitamin D deficiency there are no reports of poor bone health, or increased cancer risk associated with the ‘G’ allele of A226-2810C. No mechanism accounting for this reduction in activity is currently described 13,14.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin D Calcitriol

CYP2R1 converts vitamin D, either from the diet or generated in the skin, into its circulating form calcifediol, which is in turn converted into the bioactive form calcitriol. For those with the ‘G’ allele of A226-2810C, which is associated with reduced levels of circulating vitamin D, calcifediol, supplementation with bioactive calcitriol may ensure that appropriate vitamin D levels are maintained to deliver proper calcium uptake, maintaining bone health and ensuring normal cellular function 14.

Although the ‘G’ allele of A226-2810C has not been associated with poor health outcomes; given that the majority of us are deficient in vitamin D, supplementation is usually to be recommended to ensure both healthy calcium uptake, and that the other cellular activates dependent on vitamin D can proceed normally.

Iron

Iron is the cofactor for CYP2R1 which requires its binding in order to function correctly. For those with the ‘G’ allele of A226-2810C, which is associated with reduced levels of circulating vitamin D, supplementation with iron may ensure that CYP2R1 is functioning properly, although the importance of this SNP in bone health and other cellular functions is likely minor 10.

Indirect Nutrients:*

IngredientActive IngredientEffect
Calcium

When vitamin D binds to VDR it enables uptake of calcium from the gut. Whilst, calcium is not typically limited in the normal diet those pursuing a vegan, or dairy free diet may consider supplementation, especially if they carry the ‘G’ allele of A226-2810C 11.

Discuss this information with your doctor before taking any course of action.

T-1559C

Science Grade
C+
Musculoskeletal Health
rsID Number Major Allele Minor Allele Minor Allele Frequency (%)
rs2060793 g a 34

Risk Description

The ‘G’ allele of the SNP T-1559C in the CYP2R1 gene is associated with a small, 3% reduction in the circulating form of vitamin D calcifediol. It is unclear if this reduction in circulating vitamin D is sufficient to lead to the development of vitamin D deficiency, and there are no reports of any negative health effects associated with the ‘G’ allele of T-1559C. No mechanism accounting for this reduction in activity is currently described 15,16.

Direct Nutrients:*

IngredientActive IngredientEffect
Vitamin D Calcitriol

CYP2R1 an enzyme which converts vitamin D, either from the diet or that generated in the skin, into its circulating form calcifediol, which can in turn be converted into the bioactive form calcitriol. For those with the ‘G’ allele of T-1559C, which is associated with reduced levels of circulating vitamin D, supplementation with calcitriol may help ensure that appropriate vitamin D levels are maintained ensuring proper calcium uptake to maintain bone health and ensure normal cellular function 16.

The ‘G’ allele of T-1559C has not been associated with poor health outcomes; however, given that the majority of us are vitamin D deficient supplementation is to be recommended to ensure both healthy calcium uptake and vitamin D activity.

Iron

CYP2R1 requires iron as a cofactor in order to function correctly. For those with the ‘G’ allele of T-1559C, which is associated with reduced levels of circulating vitamin D, supplementation with iron may ensure that CYP2R1 is functioning correctly, although the exact importance of this SNP in bone health and other cellular functions is likely small 10.

Indirect Nutrients:*

IngredientActive IngredientEffect
Calcium

A major function of vitamin D binding to VDR is to ensure proper uptake of calcium from the gut. Whilst, calcium is not typically limited in the normal diet those pursuing a vegan, or dairy free diet may consider supplementation, especially if they carry the ‘G’ allele of T-1559C 11.

Discuss this information with your doctor before taking any course of action.

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