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Nutrigenetics of Sunshine vitamin (D)

Posted by : Rashida , on Sat, Jun 01, 2019
Nutrigenetics of Sunshine vitamin (D)

An individual’s vitamin D status depends on their Vitamin D uptake from food and supplements, time outside in the sun, their genetic disposition and interaction with their gut microbiome. Vitamin D deficiency has been historically defined and recently recommended by the Institute of Medicine (IOM) as a 25(OH)D of less than 20 ng/ml.

The global prevalence of vitamin D deficiency appears to be increasing (Figure.1), and the impact of this on human health is important. There is an ever-expanding list of communicable and non- communicable diseases being associated with vitamin D deficiency, including types 1 and 2 diabetes mellitus, rheumatoid arthritis, cardiovascular disease, osteoporosis, multiple sclerosis, depression, irritable bowel disease, asthma, colorectal, lung and breast cancers, upper respiratory tract infections, tuberculosis (TB), and HIV/AIDS progression and mortality (1).

Figure.1 Prevalence of low vitamin D status in adults worldwide (2)

 Different factors affecting vitamin D status:

* Wearing a sunscreen with a sun protection factor of 30 reduces vitamin D synthesis in the skin by more than 95%.(3)

* People with a naturally dark skin tone have natural sun protection and require at least three to five times longer exposure to make the same amount of vitamin D as a person with a white skin tone.(4)

* Migration can have a significant impact. White women living in the south of England had median 25(OH)D levels of 62.5 nmol/l in the summer and 39.9 nmol/l in the winter. In Asian women living in the same geographical location the median levels were considerably less at 24.9 nmol/l and 16.9 nmol/l respectively.(5)

* Women have often been found to have lower levels of 25(OH)D levels than men. Potential causes include differences in body fat composition, resulting in greater fat storage of vitamin D in women. Lower levels in women are a particular concern around the time of childbearing as the vitamin D status of women during pregnancy is an important factor in the determination of the vitamin D status in her child.(6).

Figure.2 Summary of different factors affecting vitamin D status

What happens to vitamin D inside our body?

Vitamin D is obtained from diet in the form of Ergocalciferol (Vitamin D2) or from the interaction of UVB from the sun and cholesterol in the skin to form cholecalciferol (Vitamin D3),biologically inactive form (7). This has to be converted to the active form that our  body uses. The first step in the conversion takes place in the liver, where cholecalciferol is converted into calcifediol (25 (OH)D) and then converted in the kidneys to calcitriol, the biologically active form of vitamin D. Then it is transported to the cells by binding to vitamin D receptor.

Genes and Vitamin D

Vitamin D levels have a significant hereditable component suggesting a possible role for genetics in the etiology of insufficiency. The genetic influence on vitamin D status is estimated to be around 80%, much higher than the dietary and environmental influences of around 25%. (8).Recent advances in the methodology of large-scale genetic association studies, including coordinated international collaboration, have identified associations of CG, DHCR1, CYP2R1, VDR, and CYP24A1 with serum levels of vitamin D. (9)

 

Understanding the vitamin D pathway

Figure. 4. Vitamin D pathway illustration

* The Vitamin D pathway starts with the conversion of 7-dehydrocholesterol in the skin to a precursor of vitamin D3 on exposure to sunlight.

* The DHCR7 converts 7-dehydrocholesterol to cholesterol, thereby removing the cholesterol pathway from the synthetic pathway of vitamin D3. The pre-vitamin D3 in turn is converted to vitamin D3 in a heat-dependent process.

* The first step in activation, 25-hydroxylation occurring primarily in the liver, is mediated mostly by the microsomal 25-hydroxylase, CYP2R1, and possibly to some extent by mitochondrial hydroxylase, CYP27A1.

* 25-hydroxyvitamin D (25(OH)D) is bound to the VDBP, transported to the kidneys and converted by CYP27B1 to the biologically active form 1,25-dihydroxyvitamin D3 (calcitriol), which further activates the VDR to interact with RXRG leading to the activation/suppression of the target gene expression. Calcitriol can up-regulate the expression of CYP24A1, which catabolises 25(OH)D and calcitriol to water-soluble, biologically inactive metabolites for excretion in the bile (10).

 

Various dietary factors and its influence on vitamin D levels (11)

Nutrients Influence on vitamin D levels
Calcium Reduce renal hydroxylation of 25 (OH)D to 1,25 (OH)2D
Retinol Influence binding of 1,25 (OH)2 to the VDR
Phytoestrogens Stimulate colonic synthesis of 1,25 (OH)2D from 25 (OH)D via activation of CYP27B1.
Folate Activation of CYP27B1
Calicum, phytoestrogens (genestein in soy), folate Inhibit CYP24A1 activity, and therefore degradation of 1,25 (OH) 2D.
 
Genes involved in Vitamin D metabolism, their functions and gene- specific recommendations:
 

Genes

Enzymes encoded by genes and their function

Nutrients required for effective functioning of these genes

DHCR7

DHCR7  enzyme converts 7-dehydrocholesterol to cholesterol, thereby removing the cholesterol pathway

Wheat germ, peanut, vegetable oils, almonds, yogurt, milk ,orange juice etc.

CYP2R1

CYP2R1 enzyme is involved primarily mediates the activation of conversion of cholecalciferol to calcifediol

 

 

Vitamin d3 rich foods like fatty fish such as salmon, tuna, mackerel  ,beef liver, egg yolk, etc.

CYP27A1

CYP27A1 enzyme is involved in the conversion of cholecalciferol to calcifediol

CYP27B1

CYP27B1 enzyme is involved in the conversion of calcifediol to calciferol, active form.

CYP24A1

CYP24A1 provides instruction for making an enzyme called 24-hydroxylase.This enzyme helps control the amount of active vitamin D available in the body

Fat rich foods avocado ,cheese, dark chocolate ,whole eggs, nuts .etc.

VDR

VDR enzyme helps in the transport of calcitriol to the target cell

Vitamin d2 and d3 rich foods like mushrooms grown in uv light ,fortified foods.

RXRG

Plays a role in the activation/suppression of the target gene expression

 

Protein rich foods like eggs, lean  meat, poultry, fish, milk, seeds and nuts, beans and soy foods like tofu.

Retinoic rich foods like beef, lamb, pork, poultry, fish, seafoods, dairy, eggs, fruits and vegetables.

GC

GC enzyme facilitates the transport of vitamin D to be used within the cell

 

Natural Ways to increase calcitrol and vitamin D receptor gene expression 

NUTRIENTS

FUNCTIONS

FOOD SOURCE

RXR (12)

 It is needed to produce proteins with the VDR,1,25D3 binds to the VDR, which then combines with RXR to activate gene expression.(Not all VDR dependent genes need RXR).

Beef, lamb, pork, poultry, fish, seafoods, dairy, eggs.

Lithocholic acid (13)

The secondary bile acid lithocholic acid (LCA) and its derivatives act as selective modulators of the vitamin D receptor (VDR).

Avocados,Cheese,Dark Chocolate,Whole Eggs,Fatty Fish,Nuts,Chia Seeds.,Extra Virgin Olive Oil.

Resveratrol (14)

It potentiates VDR.

peanuts, pistachios, grapes, red and white wine, blueberries, cranberries,

Forskolin (15)

It increases 1,25D3 from 25D3 in vitro.

Coleus forskohlii Herb

Non- dietary FACTORS

Anaerobic exercises

It increases calcitriol levels.

 

Parathyroid hormone (16)

It increases calcitriol.

beans, almonds, and dark green leafy vegetables

SIRT1 (17)

It potentiates VDR.SIRT1 increased the ability of VDR to associate with RXR.

apples, tea, onions, citrus

PGC-1a (18)

It potentiates VDR. It is a coactivator of the VDR, but it still needs 1,25D3.

lean meat, poultry and fish, eggs.

dairy products like milk, yoghurt and cheese.

seeds and nuts beans and legumes (such as lentils and chickpeas)

soy products like tofu.

Dexamethasone (19)

It  doesn’t compete with 1,25.

It is a drug.

Estradiol (20)

It increases VDR expression and calcitriol levels

Flax Seed, Soy, Fruits, Nuts, Dry Fruits,

Red Wine

Dopamine (21)

Its well-known role in calcium absorption.

Dairy foods such as milk, cheese and yogurt, Unprocessed meats such as beef, chicken and turkey,Omega-3 rich fish such as salmon and mackerel, Eggs, Fruit and vegetables, in particular bananas, nuts such as almonds and walnuts, dark chocolate.

 

FACTORS THAT INHIBIT THE VITAMIN D RECEPTOR(VDR):

Different factors

Functions

Caffeine (25)

It decreases VDR production

Cortisol/Glucocorticoids (26)

It decreases VDR production

Phosphatonin, heparin, thiazides (27) (28) (29)

It decreases calcitriol

Corticosteroids (30)

It decreases calcitriol

TNF (31)

It inhibits osteocalcin interaction with VDR, but not osteopontin.

TGF-beta (32)

It reduces the activation of VDR/RXR combination, which results in VDR-mediated gene expression.

Thyroid hormones (33)

It repress VDR activation

 

Dietitian’s guide to provide gene specific recommendations: (34)

Gene

Rs id

Gene Specific Recommendations

VDR

rs2228570

C allele produces shorter VDR proteins whereas T allele produces

longer VDR proteins as a result C allele carrier responds better to vitamin D supplements resulting in greater uptake of calcium in Japanese women.

Tip:Hence c allele carriers are responsive to vitamin D supplementation.

GC

rs2282679

 C  allele had reduced amounts of GC in the blood, which is thought to limit the amount of vitamin D present

Tip: Include  proteins and retinol rich foods in their diet.

CYP2R1

rs10741657

 

 

 

 

rs12794714

 

 

G allele 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

Tip: Likely to benefit by consuming foods that increases calcitriol.

T allele is associated with increased 25D levels in African

Americans  and European Americans.

Tip: Hence T allele carriers are likely to benefit by consuming calcitriol rich foods.

 

DHCR7

rs3829251

rs12785878

 

G allele is associated with decreased 25D levels.

A allele is associated with decreased 25D levels.

Tip: These carriers may benefit from consuming foods such as wheat germ, peanut, vegetable oils, almonds, yogurt, milk ,orange juice etc.

CYP27B1

rs10877012

A allele is associated with higher 25D levels in African Americans; but no association in Caucasians.

Tip: Include vitamin D3 rich foods in their diet.

CYP24A1

rs2248137

C allele is associated with decreased 25D levels.

Tip: Inclusion of fat are likely to be benefit such individuals. Fat rich foods avocado ,cheese, dark chocolate ,whole eggs, nuts .etc.

 

Conclusion:

Genes play a huge role in determining vitamin D levels and activity. It is therefore essential to eat specific nutrients according to their genes to ensure adequate vitamin D levels. Genetic testing for personalised nutrition enables an individual to understand the genetic tendency that may affect absorption, metabolism, usage and elimination of vitamin D. This information could serve as a vital tool for clinicians, especially dietitians and nutritionists in diagnosis and management of vitamin D status as it helps in understanding the causes of deficiency at a molecular level and provide more targeted and specific solutions to maintain healthy vitamin D status.

 

Acknowledgement: Ms. Harinivashini, Intern, a Postgraduate student in Food Science & Nutrition, Avinashilingam Institute of Higher Education for Women was involved in data curation related to gene specific diet recommendations.