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Genetic and Epigenetic Signature Identifies Individuals with Elevated Response to Vitamin B12 Supplementation

Vitamin B12 is essential for many aspects of human health. Deficiencies are largely caused by inadequate intake or reduced absorption, and are associated with increased incidence of neurological, cognitive and cardiovascular decline. Using a previously published dataset of B12/ folic acid supplementation in elderly individuals (GSE74548), we investigated the effect of a variant in the methylenetetrahydrofolate reductase gene (MTHFR; rs1801133) on serum B12 and folate levels at baseline and after 2 years of supplementation. As well as, the association between baseline genome‐wide DNA methylation (Infinium 450K DNA methylation chip) in peripheral blood mononuclear cells (PBMCs) and supplementation induced changes in circulating B vitamin levels. After supplementation, we observed that those with the rs1801133 CC genotype had elevated circulating B12 but not folic acid levels, relative to the rs1801133 TT genotype (P = 0.0073 and P = 0.47, respectively). Moreover, individuals with the CC genotype clustered into two distinct B12 response groups (P = 2.8 × 10−6), termed high and low responders. Additionally, we observed an enrichment of low p‐values among baseline DNA methylation patterns and change in circulating B12 levels after supplementation in CC individuals only (empirical P < 1 × 10−5). These sites are not near genetic variants or genes known to influence vitamin B12 uptake. Overall, we present evidence that epigenetic signatures at baseline may predict an individual's response to B12 supplementation and may highlight novel pathways of regulation. Elucidation and further understanding of pathways associated with elevated response to B12 supplementation, may aid in the treatment of chronically deficient individuals.