The genetics of nutritional deficiencies

By Corie Edwards

Nutrient deficiencies may seem like a thing of the past, but some may be surprised to know that there are still several key vitamins and minerals that adults in the U.S. are lacking. 

According to the CDC’s Second Nutrition Report from 2012, the top nutrients Americans are deficient in are:

• Vitamin B6 and B12
• Vitamin D, C, A, and E
• Iron
• Folate 

These nutrients are key to supporting the systems and functions of the human body.  The first line of treatment when managing someone with nutrient deficiencies is to supplement the lacking vitamin or mineral. However as many practitioners have come to find, some patient’s levels can still stay stubbornly low despite treatment.  When looking to understand this response it is important to take genetics into consideration.

I recently saw a patient that had chronically low vitamin D levels. As a Naturopath in the Pacific Northwest, this is a common patient encounter. What was interesting about this situation is that, unlike other patients, her serum levels did not rise much after supplementation of vitamin D3. I tried prescribing 15 minutes of sunbathing each day to encourage the body’s natural process for creating vitamin D. This, too, had a small, slow effect on raising her serum levels of vitamin D. 

After genetic testing, the reason for this became clear. The patient had two copies of the risk allele for CYP2R1, a gene that encodes for the enzyme responsible for the second to last step in vitamin D metabolism. This enzyme functions in the liver and helps to produce the active form of vitamin D calcitriol, which can be supplemented as a prescription drug. The risk allele caused this patient to create an enzyme that functioned at a slower rate than the normal enzyme would. I immediately prescribed calcitriol 0.25 mcg by mouth once a day to my patient and, within three months, her levels were within the optimal range of 50-70 ng/mL.      

Research has shown that certain genes have risk alleles that can increase a person’s chance of being deficient in certain nutrients. Some of the most important markers for nutritional deficiencies are genes called BCM01, FUT2-1. GC, NADSYN1/DHCR7, CYP2R1, MTHFR, and TMPRSS6. These genes affect physiological process like absorption, metabolism, and transportation of specific nutrients. Patients with risk alleles in these genes can find that they have low levels of the corresponding vitamin or nutrient despite supplementation. So how do these genes affect nutrient levels in the body?

Each gene encodes for a product that plays an important role in the body.  For instance, according to a January 2018 paper by Luigi Ferrucci, MD, Ph.D, it was reported that BCM01 encodes for a gene that can cause low conversion of carotenoids (vitamin A precursor) to retinol due to defect in enzyme function.    

Another example is the FUT2-1 gene, which can affect absorption of B12 through the GI tract. Certain genotypes have been shown to have lower B12 levels, according to by a study regarding common variants of FUT2 published in the journal Natures Genetics.  

Genes that are involved with maintaining healthy levels of vitamin D include GC, NADSYN1/DHCR7, VDR, and CYP2R1. Several studies conducted that show mutations in these genes can affect vitamin D levels through different mechanisms. These mechanisms include decreased conversion of the vitamin D metabolite to the active form, transportation of vitamin D to target tissues, and absorption.  

Another important nutrient is folate. The synthetic version of this is known as folic acid. Research shows that the MTHFR gene was found to have one risk allele associated with decreased function of the enzyme it encodes for; C677T and another that reduced function when associated with C677T called A1298C. The MTHFR gene encodes for an enzyme called methylenetetrahydrofolate reductase, which converts 5-10-methylene tetrahydrofolate to 5-methyltetrahydrofolate (5-MTHFR). 5-MTHFR is used as a co-substrate to recycle homocysteine to methionine. Iron deficiencies have been linked to certain risk alleles found in the TMPRSS6 gene. 

Other research has shown that people with a risk allele in this gene have been shown to have an increased risk for a lower rate of iron absorption.  

Understanding a patient’s individual biochemistry can not only help to identify potential risk for deficiencies, but also to develop a more effective treatment plan.  For example, if the risk allele affects enzyme function causing a decrease in conversion of a substrate into the next form, it may benefit the patient to supplement with the final product of that metabolic pathway. However if the risk allele causes a decrease in absorption of a specific nutrient then a different delivery system, like injecting the nutrient or supplementing with a liposomal form is often enough to quickly fix the problem. 

A common defect in the metabolic pathway of nutrient deficiencies is with transportation of the vitamin to specific tissues. Genes that encode for transportation proteins can create a product that may not bind a nutrient as easily, this can cause a decrease in supply to the tissue despite the patient taking in normal amounts. Lower more frequent doses of the nutrient may help to give the body a constant supply of the much needed vitamin or mineral without overwhelming the transportation system.    

Even in established societies with ready access to food and nutrients, people can be deficient in key nutrients. Genetics may play a role in this causing certain people to be more susceptible to lacking a specific vitamin or mineral. Understanding the person’s specific genetic predisposition can help a practitioner to develop a more beneficial nutritional treatment plan. 

References

• CDC’s Second Nutrition Report. (2012, March 27). Retrieved June 6, 2018, from https://www.cdc.gov/nutritionreport/index.html
• Ferrucci L et al. “Common Variation in the B-Carotene 15, 15’-Monooxygenase 1 Gene Affects Circulating Levels of Carotenoids: A Genome-wide Association Study.” The American Journal of Human Genetics. 2009; 84, 123-133.
• Borel P et al. “Genetic Variations Involved in Interindividual Variability in Carotenoid Status.” Mol Nutr Food Res. 2012; 56(2): 228-40.
• Hazra A et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat. Genet. 2008; 40:1160–1162.
• Foucan L et al. Polymorphisms in GC and NADSYN1 Genes are associated with vitamin D status and metabolic profile in non-diabetic adults. BMC Endocrine Disorders. 2013; 13:36.
• Ahn J et al. Genome-wide association study of circulating vitamin D levels. Human Molecular Genetics. 2010; 19(13) 2739-2745.
• Hara N et al. Molecular identification of human glutamine- and ammonia-dependent NAD synthetases. Carbon-nitrogen hydrolase domain confers glutamine dependency. J. Biol. Chem. 2003; 278(13):10914-10921.
• Wassif CA et al Mutations in the human sterol Δ7-reductase gene at 11q12–13 cause Smith–Lemli–Opitz syndrome. Am. J. Hum. Genet. 1998; 63:55–62.
• Wang T et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010; 376(9736):180-188.
• Cheng JB et al. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A. 2004; 101:7711–7715.
• Nissen J et al. Vitamin D Concentrations in Healthy Danish Children and Adults. PLOS One. 2014; 9(2):e89907
• Wagner C. Biochemical role of folate in cellular metabolism. In: Bailey LB, editor. Folate in health and disease.  New York, NY: Marcel Dekker Inc.; 1995. p. 23–42. 
• Bailey LB and JF Gregory III. Polymorphisms of Methylenetetrahydrofolate Reductase and Other Enzymes: Metabolic Significance, Risks and Impact on Folate Requirement. J Nutr. 1999; 129(5):919-22.
• Van der Put NM et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998; 62(5):1044–51.
• Stover PJ. Polymorphisms in 1-Carbon Metabolism, Epigenetics and Folate-Related Pathologies. J. Nutrigenet Nutrigenomics. 2012; 4(5):293-305.
• Benyamin B et al. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nature Genetics 2009; 41:1173-1175.
• Chambers JC et al. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nature Genetics 2009; 41:1170-1172.