The Nutrigenetics of Vitamin B12

Vitamin B₁₂ refers to a group of organic compounds known as cobalamins, which play essential roles in hematopoiesis, DNA synthesis, cognition, mood, nerve health and cardiovascular health.^1,2  By supporting a process called methylation, this nutrient  supports the metabolism of homocysteine and the formation of neurotransmitters and other essential compounds.¹  

B₁₂ status is a complex trait that is determined not only by dietary intake, but by many genetic and physiological variables.  Evidence of a profound genetic influence came from a Swedish study of 215 monozygotic and dizygotic twin pairs, which estimated a heritability of 59%.³  Candidate gene and genome-wide scans point to a growing number of genetic loci related to cobalamin absorption, transport and metabolism.^4-6  While B₁₂ status is complex and polygenic (involving many genes), you can gain clinical insight by assessing two single nucleotide polymorphisms using widely available genetic tests:

FUT2 (Fucosyltransferase 2)

In a genome wide scan of more than 528,000 genetic variants, a 2008 study detected the strongest signals from variants in FUT2, accounting for roughly 3% of the inter-individual variation in plasma cobalamin levels.⁶  This gene participates in host-microbe interactions in the gut, which are believed to mediate its effects on cobalamin absorption and transport.  Polymorphisms in FUT2 may enhance or diminish cobalamin status, depending on the variant.  Among the most robust genetic markers is the 428 G/A nonsecretor variant allele (W143X variant; rs601338).⁵ Coincidentally, this is the same variant that confers resistance to norovirus, by altering viral interactions with the gut lining.⁷

TCN2 (Transcobalamin)

Approximately 20-25% of circulating cobalamin forms a complex with transcobalamin, which delivers the vitamin to cells.  The complex (holo-transcobalamin; holo-TC), which represents the bioavailable fraction in blood, enters cells via receptor-mediated endocytosis.⁸   The G776C (rs1801198) SNP reduces cellular transcobalamin expression and plasma concentrations, correlating with lower tissue disposition.^9-11

Lab testing

Further assessment might be worthwhile for carriers of any of these variants to confirm the need for nutritional support:

• Serum B₁₂  is a widely available assay that can rule out problems with absorption (FUT2), but not with cellular uptake (TCN2).
• Methylmalonic acid (MMA), the substrate for the MCM enzyme, accumulates when adenosylcobalamin levels in the mitochondria are low.  MMA is clinically useful as an intracellular (mitochondrial) marker that inversely correlates with total B₁₂ status.
• Holo-transcobalamin levels reflect the active circulating fraction of vitamin B₁₂ that is bound to transcobalamin.  

Selecting a supplement

Cobalamins exist in multiple forms in the body, with appreciable endogenous inter-conversion.^1,2  Any of the following options will improve B₁₂ status when given at a sufficient dose, but several functional distinctions are worth noting.

Hydroxycobalamin (or hydroxocobalamin) is a predominant cobalamin in food and is commonly used in injectable preparations.^1,2  It undergoes extensive endogenous conversion to the active coenzymes, methylcobalamin and adenosylcobalamin.^1,12-14

Cyanocobalamin is commonly used in solid dosage formats due to its low cost.  It is converted to hydroxycobalamin in the body, but the coincident release of a cyanide group is a good reason to consider other forms.

Methylcobalamin comprises 60-80% of circulating B₁₂.^2,12   It serves as the coenzyme for methionine synthase, which converts homocysteine to methionine in the methylation cycle.¹

Adenosylcobalamin is a cofactor for methylmalonyl-CoA mutase (MCM), a TCA cycle enzyme whose function declines with age.^1,12  This is the major mitochondrial cobalamin, with unique relevance to cellular energy output and muscle health.   

Further Reading  

A review on vitamin B12-related polymorphisms  by Surendran, S., et al.  Genes Nutr 13, 2 (2018).  

Vitamin B12 Fact Sheet for Health Professionals from the NIH Office of Dietary Supplements

Patient-friendly resources

Vitamin B12 Fact Sheet for Consumers from the NIH Office of Dietary Supplements

Best food sources of B12 (printer-friendly)

References

1. Brody T. Nutritional Biochemistry. 2^nd ed. San Diego: Academic Press; 1999.
2. Gropper SS, Smith JL. Advanced Nutrition and Human Metabolism. 6^th ed. Belmont, CA: Wadsworth; 2012.
3. Nilsson SE et al. Heritabilities for fifteen routine biochemical values: findings in 215 Swedish twin pairs 82 years of age or older. Scand J Clin Lab Invest. 2009;69(5):562–9.
4. Quadros EV. Advances in the understanding of cobalamin assimilation and metabolism. Br J Haematol. 2010;148(2):195–204.
5. Surendran S et al. An update on vitamin B12-related gene polymorphisms and B12 status. Genes Nutr 13, 2 (2018).  
6. Hazra AB et al. Common Variants of FUT2 are Associated with Plasma Vitamin B12 Levels. Nat Genetics, Sept. 7, 2008
7. Nordgren J, Svensson L. Genetic Susceptibility to Human Norovirus Infection: An Update. Viruses. 2019 Mar 6;11(3):226.  
8. Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr. 2011 Jul;94(1):359S-365S.  
9. Castro R, et al. The TCN2 776CNG polymorphism correlates with vitamin B(12) cellular delivery in healthy adult populations. Clin Biochem. 2010 May;43(7-8):645-9. 
10. Namour F, et al. Isoelectrofocusing phenotype and relative concentration of transcobalamin II isoproteins related to the codon 259 Arg/Pro polymorphism. Biochem Biophys Res Commun 1998;251:769–74.  
11. Namour F, et al. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood 2001;97:1092–8. 
12. Farquharson J, Adams JF. Br J Nutr 1976;36(1):127-36.
13. Kim HI, et al. Ann Surg Oncol 2011;18(13):3711-7.
14. van Asselt DZ, et al. J Gerontol A Biol Sci Med Sci 2001;56(12):M775-9.