Vitamin B12 is essential for healthy nerve cells, DNA production, and red blood cell formation. Many people suffer from Vitamin B12 deficiency (especially in the vegan community) which can cause anemia, neurological problems, and other health issues.
This blog post explores how genetic variants affect Vitamin B12 absorption, transport, and conversion.
Vitamin B12 Metabolism Overview
Vitamin B12 metabolism involves several complex steps:
- absorption in the gut
- transport through the bloodstream
- conversion into active forms within the body.
Absorption
Vitamin B12 is absorbed in the small intestine. It comes from animal products like meat, dairy, and eggs, or, for vegans, dedicated supplements. In the stomach, hydrochloric acid separates Vitamin B12 from proteins in food. Then, Vitamin B12 binds to intrinsic factor, a protein produced in the stomach, allowing it to be absorbed in the small intestine.
Hydrochloric acid is a strong digestive acid produced by the stomach. It helps break down food and releases Vitamin B12 from the proteins it is bound to. Intrinsic factor is a protein produced by the special cells of the stomach (parietal cells). It binds to Vitamin B12 and is essential for its absorption in the small intestine. Without intrinsic factor, Vitamin B12 cannot be effectively absorbed.
Transport
After absorption, Vitamin B12 binds to transcobalamin, a transport protein that carries it through the bloodstream to various cells and tissues.
Transcobalamin is a protein that binds to Vitamin B12 and facilitates its transport from the intestines to the cells that need it. There are three types of transcobalamin: I, II, and III. Transcobalamin II is the most important for delivering Vitamin B12 to the cells.
Transcobalamin-bound Vitamin B12 (holotranscobalamin) is the bioavailable form that cells can use.
Conversion
In cells, Vitamin B12 is converted into its active forms: methylcobalamin and adenosylcobalamin. Methylcobalamin is involved in DNA synthesis and maintaining healthy nerve cells, while adenosylcobalamin is crucial for energy production and fat metabolism.
Genetic Variants Affecting Absorption
Genetic polymorphisms can significantly impact absorption of Vitamin B12 in the gut.
FUT2, TCN2
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FUT2 (Fucosyltransferase 2): This gene affects the secretion of H antigen in the gut, which is crucial for the proper binding and absorption of Vitamin B12. Individuals with certain FUT2 variants have a higher risk of Vitamin B12 deficiency due to impaired absorption.
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TCN2 (Transcobalamin 2): Variants in the TCN2 gene can influence the binding efficiency of transcobalamin to Vitamin B12. Some TCN2 polymorphisms are associated with lower levels of holotranscobalamin, which can lead to poor Vitamin B12 status.
These genetic differences can increase the risk of deficiency and related health issues.
Genetic Variants in Vitamin B12 Transport
Transport of Vitamin B12 through the bloodstream is also influenced by genetic variants.
TCN2, MTRR
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TCN2 (Transcobalamin 2): As previously mentioned, TCN2 is crucial for Vitamin B12 transport. Variants in this gene can reduce the ability of transcobalamin to bind and carry Vitamin B12 effectively, which results in a lower availability of the vitamin for cellular uptake.
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MTRR (Methionine Synthase Reductase): This gene is involved in the regeneration of methionine synthase, an enzyme that uses Vitamin B12. Variants in MTRR can affect the transport and utilization of Vitamin B12.
These genetic variants can result in less efficient transport and lower levels of bioavailable Vitamin B12 in the body.
Genetic Variants in Conversion and Utilization
Once Vitamin B12 is transported to cells, it must be converted into its active forms. Genetic variants can influence this conversion process.
MTR, MTRR, MTHFR
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MTR (Methionine Synthase): This gene encodes an enzyme that requires methylcobalamin to function. Variants in MTR can impact DNA synthesis and neurological health.
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MTRR (Methionine Synthase Reductase): As mentioned, MTRR is essential for regenerating methionine synthase. Variants here can impact methylcobalamin production.
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MTHFR (Methylenetetrahydrofolate Reductase): This gene influences folate metabolism and homocysteine levels. MTHFR variants can affect methylcobalamin production and utilization.
Folate (Vitamin B9) and Vitamin B12 work closely together in various metabolic processes. Folate is essential for the synthesis of DNA and the metabolism of amino acids. Homocysteine is an amino acid that, when present in high levels, can be a risk factor for cardiovascular disease and other health problems.
Reference table
For all the variants in this table, the alternative allele (denoted by Alt) has been associated with increased circulating Vitamin B12 levels.
| Gene | rsID | Ref | Alt |
|---|---|---|---|
| FUT2 | rs492602 | A | G |
| FUT2 | rs602662 | G | A |
| FUT6 | rs3760775 | G | T |
| FUT6 | rs78060698 | G | A |
| TCN1 | rs34324219 | C | A |
| TCN2 | rs1131603 | T | C |
| CUBN | rs12780845 | A | G |
| MMAA | rs2270655 | G | C |
References:
- Aditi et al. Common variants of FUT2 are associated with plasma vitamin B12 levels
- Nongmaithem et al. GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians
- Tanwar et al. Common variant in FUT2 gene is associated with levels of vitamin B(12) in Indian population
- Tanaka et al. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations