Oct 14, 2023
Vitamin B12, also known as cobalamin, is an important water-soluble micronutrient that must be taken by humans to maintain health. Nutritional deficiency of vitamin B12 has been associated with many complications such as increased risk of macrocytic anemia, neuropsychiatric symptoms, cardiovascular diseases and the onset of different types of cancer. B12 deficiency is clinically associated with megaloblastic anemia and neurodegenerative disorders, and is also linked to cardiovascular diseases thought to be mediated through hyperhomocysteinemia (Surendran, S. et al., 2018). Due to low B12, weakness, fatigue, and amnesia are common. Vitamin B12 is found in animal products such as meat, eggs and shellfish.
Vitamin B12 and TCN1/TCN2 Gene Relationship
The transcobalamin 1 (TCN1) gene encodes transcobalamin I, a vitamin B12-binding protein. TCI plays a role in facilitating the entry of vitamin B12 into cells via receptor-mediated endocytosis. The TCN2 gene, also known as transcobalamin 2, has the function of making the vitamin B12-binding protein called transcobalamin II (TC), which is found in human serum. TC plays a role in the absorption and transport of vitamin B12 into the cell. Only 10-20% of vitamin B12 binds to TC; the remainder binds to transcobalamin 1 (holo-haptocorrin) (Surendran, S. et al., 2018).
Vitamin B12 and MTRR Gene Relationship
The Methionine synthase reductase (MTRR) enzyme is encoded by the MTRR gene. It is responsible for maintaining adequate levels of active vitamin B12 (methylcobalamin), which keeps the methionine synthase enzyme active (Surendran, S. et al., 2018).
Vitamin B12 and MTHFR Gene Relationship
The MTHFR gene encodes the information needed to produce an enzyme called methylenetetrahydrofolate reductase. This enzyme is important for processing amino acids and creating proteins. Genetic variations in the MTHFR gene result in decreased activity of the enzyme produced and are associated with a number of diseases and conditions, including cardiovascular disorders, neurological defects, certain types of cancer, psychiatric disorders, diabetes and pregnancy complications (W Boughrara et al., 2015).
Vitamin B 12 and FUT 2 Gene Relationship
Common variants in exon 2 of FUT2 (rs602662, rs492602, and FUT2 haplotype) have been associated with higher vitamin B-12 status. There are two hypotheses to explain the relationship between FUT2 and vitamin B-12 status. First, FUT2 variants reduce the risk of vitamin B-12 malabsorption due to Helicobacter pylori infection and associated gastritis by reducing H-type antigen production and function. The second hypothesis is that variants of FUT2 increase the secretion of gastric intrinsic factor, a fucosylated glycoprotein required for vitamin B-12 absorption (Zinck, J. W. et al., 2015).
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VITAMIN B12 |
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Genes |
rs |
Minor Allel |
Minor Allel Description |
Reference |
|
MTHFR |
rs1801133 |
T |
Increased relative risk for vitamin B12 deficiency and hyperhomocysteinemia.
|
(Al-Batayneh, K. M. et al., 2018)
|
|
MTRR |
rs1801394 |
G |
Increased risk of hyperhomocysteinemia associated with B12 and folate deficiency relative risk.
|
|
|
TCN1 |
rs526934 |
G |
Increased relative risk for low plasma B12 level. |
(Nongmaithem SS, et al., 2017)
|
|
TCN2 |
rs9606756 |
G |
Increased relative risk for low plasma B12 level. |
|
|
FUT2 |
Rs602662 |
G |
Decreased relative risk for low plasma B12 level. |
|
The table above contains genes and polymorphisms that play a role in vitamin B12 metabolism. According to studies, individuals with the TT genotype of the MTHFR 677C>T variant are highly prone to vitamin B12 deficiency. The TT genotype and the presence of the T allele were found to be significantly associated with low vitamin B12 levels (Al-Batayneh, K. M. et al., 2018).
Carriers of the 'G' allele of the TCN1 rs526934 variant were found to have lower circulating vitamin B12 concentrations compared to carriers of the 'A' allele (Nongmaithem SS, et al., 2017).
The MTRR enzyme has a role in keeping B12 in an active state. The most common polymorphism, rs1801394 (A66G), reduces the activity of the enzyme. Therefore, individuals with the GG allele were associated with lower levels of B12 (Miasko, M. H. et al., 2020).
TCN2 rs9606756 polymorphism is more common in patients with pernicious anemia, associated with low vitamin B12 levels (Lahner, E. et al., 2015).
A strong association was found between FUT2 rs602662 polymorphism and plasma vitamin B12. Individuals carrying this variant have been shown to have lower B12 levels (Hazra, A. et al., 2008).
REFERENCES
Al-Batayneh, K. M., Al Zoubi, M. S., Shehab, M., Al-Trad, B., Bodoor, K., Khateeb, W. A., A. Aljabali, A. A., Hamad, M. A., & Eaton, G. (2018). Association between MTHFR 677C>T Polymorphism and Vitamin B12 Deficiency: A Case-control Study. Journal of Medical Biochemistry, 37(2), 141-147. https://doi.org/10.1515/jomb-2017-0051
Hazra, A., Kraft, P., Selhub, J., Giovannucci, E. L., Thomas, G., Hoover, R. N., Chanock, S. J., & Hunter, D. J. (2008). Common variants of FUT2 are associated with plasma vitamin B12 levels. Nature Genetics, 40(10), 1160. https://doi.org/10.1038/ng.210
Lahner, E., Gentile, G., Purchiaroni, F., Mora, B., Simmaco, M., & Annibale, B. (2015). Single nucleotide polymorphisms related to vitamin B12 serum levels in autoimmune gastritis patients with or without pernicious anaemia. Digestive and Liver Disease, 47(4), 285-290. https://doi.org/10.1016/j.dld.2015.01.147
Miasko, M. H., Smail, S. W., Karim, A. Y., Qadir, M. K., Bapir, A. A., Omar, S. A., Ismail, I. I., Taha, O. S., Khudhur, Z. O., Jalal, K. F., Mustafa, M. Q., Awla, H. K., Saeed, M., & Safdar, M. (2020). Association study of polymorphisms at A66G (rs1801394) of MTRR gene and autism spectrum disorders in a Kurdish population. Gene Reports, 21, 100949. https://doi.org/10.1016/j.genrep.2020.100949
Nongmaithem SS, Joglekar CV, Krishnaveni GV, Sahariah SA, Ahmad M, Ramachandran S, Gandhi M, Chopra H, Pandit A, Potdar RD, H D Fall C, Yajnik CS, Chandak GR. GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians. Hum Mol Genet. 2017 Jul 1;26(13):2551-2564. doi: 10.1093/hmg/ddx071. Erratum in: Hum Mol Genet. 2017 Jul 1;26(13):2589. PMID: 28334792; PMCID: PMC5886186. https://pubmed.ncbi.nlm.nih.gov/28334792/
Surendran, S., Adaikalakoteswari, A., Saravanan, P., Shatwaan, I. A., Lovegrove, J. A., & Vimaleswaran, K. S. (2018). An update on vitamin B12-related gene polymorphisms and B12 status. Genes & Nutrition, 13. https://doi.org/10.1186/s12263-018-0591-9
W Boughrara, M Aberkane, M Fodil, A Benzaoui, S Dorgham, F Zemani, C Dahmani, E Petit Teixeira, A Boudjema. Impact of MTHFR rs1801133, MTHFR rs1801131 and ABCB1 rs1045642 polymorphisms with increased susceptibility of rheumatoid arthritis in the West Algerian population: A case-control study. Acta Reumatol Port. Oct-Dec 2015;40(4):363-71. https://pubmed.ncbi.nlm.nih.gov/26922200/
Zinck, J. W., De Groh, M., & MacFarlane, A. J. (2015). Genetic modifiers of folate, vitamin B-12, and homocysteine status in a cross-sectional study of the Canadian population. The American Journal of Clinical Nutrition, 101(6), 1295-1304. https://doi.org/10.3945/ajcn.115.107219