Novel genetic variants associated with stable isotope-based vitamin B 12 bioavailability measurements in healthy Indian adults.
Level 3 - non-randomized controlled study
Prospective observational pharmacokinetic and genetic association cohort study.
PubMed 40840787 · doi:10.1016/j.ajcnut.2025.08.005
What was done
In 104 young, healthy Indian adults, baseline functional vitamin B12 markers (total B12 and holotranscobalamin) were measured using chemiluminescence immunoassays. Participants were administered an oral dose of [13C]-labeled vitamin B12 (cyanocobalamin). Plasma bioavailability was estimated through nonlinear mixed-effects modeling of time-concentration profiles using a modified 2-compartment pharmacokinetic model. Associations with genetic variants in vitamin B12 pathway genes were assessed, and polygenic risk scores (PRSs) were calculated.
What was found
Mean measured vitamin B12 bioavailability was 52% ± 16%, showing a 4.4-fold interindividual range. Bioavailability was significantly associated with 85 single nucleotide polymorphisms (SNPs) in or near 14 genes, including 5 previously identified SNPs and 80 novel variants. A bioavailability-PRS explained 72% (95% CI: 60%, 81%) of the variance within the cohort and 55% in 3-fold cross-validation. At the first quartile threshold, the PRS identified individuals requiring supplementation with a positive predictive value of 0.32.
Why it matters
This study provides direct pharmacokinetic evidence using stable isotope labeling that genetic variation contributes substantially to interindividual differences in vitamin B12 absorption. Identifying these variants helps explain why some individuals develop deficiency or insufficiency despite having adequate dietary intake.
Limits
The sample size was small (n = 104) for genetic discovery and polygenic risk score development, increasing the risk of statistical overfitting without an independent external replication cohort. The study was restricted to young, healthy Indian adults, limiting generalizability to other age groups, ancestries, or individuals with gastrointestinal disorders. The positive predictive value for clinical supplementation need was low (0.32).
Cited by
- supports Genetic polymorphisms can impair the processing and absorption of cyanocobalamin forms of vitamin B12.