Comments on "Vitamin Pharmacogenomics: New Insight into Individual Differences in Diseases and Drug Responses".

Dear Editor,

I would like to offer some comments on the excellent article by Hai-Yan He and colleagues published in Genomics, Proteomics & Bioinformatics on 1st April 2017 [1]. The authors include, in the list of genetic polymorphisms that have an effect on vitamins, the low concentrations of cellular and plasma vitamin B12 in GG carriers of SNP rs602662 (772 G > A) in the gene encoding fucosyltransferase 2 (FUT2).

The G allele of FUT2 rs602662 is the ancestral allele, and as reviewed in the article by He and colleagues, has been recognised in various genome-wide association study (GWAS) analyses as linked with lower plasma levels of vitamin B12 [1]. This SNP is in strong linkage disequilibrium with the FUT2 W143X nonsense variant (rs601338) [2], which is known as the primary allele for non-secretor status of ABH blood group antigens [3]. The ancestral (G) allele of SNP rs601338 allows for normal translation of FUT2 (ABH secretor), whereas the variant A allele, linked with the missense variant rs602662(A), results in a premature stop codon in FUT2 and a truncated, dysfunctional FUT2 enzyme, leading to the ABH non-secretor phenotype.

The association between FUT2 and vitamin B12 is likely to result from ABH non-secretor status, as the association between plasma vitamin B12 concentration and the FUT2 rs492602 (in perfect linkage disequilibrium with rs601338) is found to be stronger than that for rs602662 [3].

The secretor phenotype was originally believed to be associated with reduced plasma B12 due to an association with Helicobacter pylori-induced gastritis [4], but this was refuted in a later study by Oussalah and colleagues which investigates the influence of FUT2 polymorphism on H. pylori serologic status [5]. A subsequent paper by Chery et al suggests that FUT2 phenotype worsens B12 status by decreasing gastric intrinsic factor (GIF) secretion via a mechanism related to H-type fucosylation, particularly in the presence of GIF mutations, and is unrelated with H. pylori-induced gastritis [6].

Interestingly, a recent GWAS analysis by Nongmaithem and colleagues based on Indians in the Pune Maternal Nutrition Study has identified allele-specific differences for rs78060698 in FUT6 [7]. This variant is found to differentially influence the binding affinity of hepatocyte nuclear factor 4α (HNF4α), and the knockdown of HNF4α may repress the expression of FUT3, FUT5, and FUT6. This in turn would affect production of the fucose moiety in the glycan structure secreted in the intestinal tract, which has an important role in maintaining host-microbial interaction, as well as microbial abundance and diversity. Thus, the rs78060698 variant could play a part in mediation of intestinal host-microbial interaction, leading to alteration of plasma B12 concentrations. Given the influence of the FUT2 ABH non-secretor variant on plasma B12 levels, and also the difference between vegetarians and non-vegetarians [8], this seems entirely feasible. Nongmaithem et al also consider the possibility of an influence of FUTs on B12 concentrations, which may be mediated through the glycosylation of B12-binding proteins and their receptors including transcobalamin I, GIF, cubilin, and CD320. The authors state however that the mechanism through which the FUTs act upon these B12-binding proteins and their receptors is unclear and needs to be investigated further.

Competing interests

The author has declared that no competing interests exist.