Vitamin B12

Vitamin B12, Secretor Status and Ancestry Raw Data

The Opus 23 genetic interpretation software [1] checks for ABH secretor status as part of the hereditary genetics algorithms. Knowing whether your client is a secretor or non-secretor is important for many reasons, one being that non-secretors have increased levels of serum vitamin B12. This is a well known association: at least five GWAS studies found SNPs in FUT2 show the strongest statistical association with circulating vitamin B12 [2-6]. Two of these studies also report a 10-25% increase in circulating total vitamin B12 concentration in homozygotes for the common non-secretor alleles, as determined by the FUT2 genotype of the nonsense stop-gain mutation W143X, rs601338. The mechanism for this is however unclear.

Previously theories have included the influence of H. pylori infection, which has been associated with vitamin B12 deficiency. [7,8] Some authors have proposed that FUT2 genotype can influence the extent to which H. pylori attaches to gastric mucosa and influences vitamin B12 absorption. [9, 10] This was refuted by a subsequent study in 2012, which found that secretor status as determined by FUT2 variation correlates with plasma vitamin B12 concentrations, but is independent of H. pylori serotype. [11]

Chery et. al. Proposed that FUT2 genotype could affect the glycosylation status of another vitamin B12 transporter, gastric intrinsic factor (GIF) [12]. This was a small study however, and although a potential effect was observed on GIF secretion and glycosylation according to FUT2 rs601338 genotype, the GIF phenotypes of the FUT2 rs601338 GA heterozygotes more closely aligned with those of the non-secretor genotype (AA) than those with the secretor genotype (GG). It is currently unclear to what extent FUT2 genotype influences GIF secretion and thereby alters vitamin B12 concentration in the general population.

It is important to note that all the above mentioned studies measured only total circulating vitamin B12, which does not distinguish the proportion of B12 bound to its two separate carrier proteins, transcobalamin and haptocorrin. Haptocorrin, also known as transcobalamin-1 (TCN1), is a glycoprotein produced by the salivary glands of the oral cavity in response to ingestion of food. This protein binds strongly to vitamin B12 in the mouth to protect it from the acidic environment of the stomach. Haptocorrin also circulates and binds approximately 80% of circulating B12, rendering it unavailable for cellular delivery by transcobalamin II. These carrier proteins carry significantly different quantities of vitamin B12 in blood, and have different biological properties: transcobalamin II delivers vitamin B12 to all tissues, while vitamin B12 carried by haptocorrin is ultimately returned to the gut. In a recent paper on a GWAS study by Velkova et. al. using The Trinity Student Study population of 2,524 subjects in Ireland, the authors hypothesized that the expression of functional FUT2 enzyme could influence total circulating vitamin B12 concentration by altering the glycosylation of haptocorrin. This is the first study to assess the relationship between ‘active’ B12, total B12 and the FUT2 secretor status variant. [13]

The authors reported that FUT2 genotype influences the concentration of haptocorrin-bound vitamin B12 to a far greater extent than transcobalamin-bound vitamin B12. This is consistent with FUT2 exerting influence via its fucosylation function, as haptocorrin is a glycosylated protein and transcobalamin is not. They also suggest that FUT2 activity impacts the intra-organismal recycling of vitamin B12, not the absorption and assimilation of the vitamin from the diet.

In both the H. pylori and the GIF models described above, FUT2 genotype would alter the pool of vitamin B12 absorbed from the gut. As vitamin B12 transported from the gut binds to transcobalamin in plasma, these models are not consistent with the data from Velkova et. al., which shows that FUT2 genotype influences the concentration of haptocorrin-bound vitamin B12 to a far greater extent than transcobalamin-bound vitamin B12.

The connection between secretor status and B12 levels is consistent with FUT2 exerting influence via its fucosylation function on B12 carriers, as haptocorrin is a glycosylated protein and transcobalamin is not. It also suggests that FUT2 activity impacts the intra-organismal recycling of vitamin B12, not the absorption and assimilation of the vitamin from the diet. This could be the reason why the standard test for vitamin B12 has significant false positive and false negative rates: only ~20% of circulating vitamin B12 (holoTC) represents the “active” bioavailable form, meaning that the most commonly ordered clinical test for vitamin B12 mainly measures the holoHC, which could mask an existing vitamin B12 deficiency. When evaluating or confirming vitamin B12 deficiency, additional markers of vitamin B12-dependent enzyme activity such as methylmalonic acid (MMA) and total homocysteine are also problematic. FUT2 secretor status may therefore be useful when considering the overall B12 status of an individual, and non-secretors may appear to have falsely elevated serum total B12 when compared with active B12.

Opus 23 handles a range of raw data files, however Ancestry.com and Genos data files do not include the rs601338 SNP, which denotes the non-secretor mutation when homozygous. When only these data files are loaded Opus 23 looks for another SNP on FUT2 that is reported in Ancestry.com and Genos raw data files, and which is in perfect linkage disequilibrium with rs601338. This will give you the client’s imputed secretor status, and therefore indications for interpreting serum vitamin B12 tests. Opus 23 also checks for another FUT2 non-secretor SNP found only in Asians and not in Caucasians when looking for secretor status.

References: 

1. Opus 23 Pro genetic analysis and reporting software by Dr P. D’Adamo www.opus23.com.

2 .Hazra, A., Kraft, P., Selhub, J., Giovannucci, E.L., Thomas, G., Hoover, R.N., Chanock, S.J. and Hunter, D.J. (2008) Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet, 40, 1160-1162. PMID 18776911.

3. Lin, X., Lu, D., Gao, Y., Tao, S., Yang, X., Feng, J., Tan, A., Zhang, H., Hu, Y., Qin, X. et al. (2012) Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men. Hum Mol Genet, 21, 2610-2617. PMID 22367966.

4. Tanaka, T., Scheet, P., Giusti, B., Bandinelli, S., Piras, M.G., Usala, G., Lai, S., Mulas, A., Corsi, A.M., Vestrini, A. et al. (2009) Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet, 84, 477-482. PMID 19303062.

5. Grarup, N., Sulem, P., Sandholt, C.H., Thorleifsson, G., Ahluwalia, T.S., Steinthorsdottir, V., Bjarnason, H., Gudbjartsson, D.F., Magnusson, O.T., Sparso, T. et al. (2013) Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet, 9, e1003530. PMID 23754956.

6. Hazra, A., Kraft, P., Lazarus, R., Chen, C., Chanock, S.J., Jacques, P., Selhub, J. and Hunter, D.J. (2009) Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet, 18, 4677-4687. PMID 19744961

7. Kaptan, K., Beyan, C., Ural, A.U., Cetin, T., Avcu, F., Gulsen, M., Finci, R. and Yalcin, A. (2000) Helicobacter pylori–is it a novel causative agent in Vitamin B12 deficiency? Arch Intern Med, 160, 1349-1353. PMID 10809040.

8. Carmel, R., Perez-Perez, G.I. and Blaser, M.J. (1994) Helicobacter pylori infection and food-cobalamin malabsorption. Dig Dis Sci, 39, 309-314. PMID 8313813.

9 Ikehara, Y., Nishihara, S., Yasutomi, H., Kitamura, T., Matsuo, K., Shimizu, N., Inada, K., Kodera, Y., Yamamura, Y., Narimatsu, H. et al. (2001) Polymorphisms of two fucosyltransferase genes (Lewis and Secretor genes) involving type I Lewis antigens are associated with the presence of anti-Helicobacter pylori IgG antibody. Cancer Epidemiol Biomarkers Prev, 10, 971-977. PMID 11535550.

10 Magalhaes, A., Rossez, Y., Robbe-Masselot, C., Maes, E., Gomes, J., Shevtsova, A., Bugaytsova, J., Boren, T. and Reis, C.A. (2016) Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding. Sci Rep, 6, 25575. PMID: 27161092.

11. Oussalah, A., Besseau, C., Chery, C., Jeannesson, E., Gueant-Rodriguez, R.M., Anello, G., Bosco, P., Elia, M., Romano, A., Bronowicki, J.P. et al. (2012) Helicobacter pylori serologic status has no influence on the association between fucosyltransferase 2 polymorphism (FUT2 461 G->A) and vitamin B-12 in Europe and West Africa. Am J Clin Nutr, 95, 514-521. PMID 22237057.

12. Chery, C., Hehn, A., Mrabet, N., Oussalah, A., Jeannesson, E., Besseau, C., Alberto, J.M., Gross, I., Josse, T., Gerard, P. et al. (2013) Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie, 95, 995-1001. PMID 23402911.

13. Velkova A, Diaz JEL, Pangilinan F, et. al; The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin (holoHC), but not holo-transcobalamin (holoTC), and is associated with haptocorrin glycosylation, Hum Mol Genet, Volume 26, Issue 24, 15 December 2017, Pages 4975–4988. PMID 29040465.

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