Publications
Novel genetic variants associated with stable isotope-based vitamin B(12) bioavailability measurements in healthy Indian adults.
Sivadas, Ambily; Devi, Sarita; Pasanna, Roshni M.; Dutta, Ujjaini; Sachdev, Harshpal Singh; Kurpad, Anura V. BACKGROUND: Vitamin B(12) deficiency is a prevalent health concern that can lead to hematological and neurological disorders. Despite adequate intake, vitamin B(12) deficiency/insufficiency can arise due to interindividual differences in absorption and metabolism influenced by genetic factors, gastrointestinal health, and medications. Although previous studies have explored the genetic basis of circulating vitamin B(12) concentration, they have not been validated using precise, stable, isotope-based measurements of vitamin B(12) bioavailability. OBJECTIVES: To measure the plasma bioavailability of an oral dose of [(13)C]-labeled vitamin B(12) (cyanocobalamin) using 2-compartment pharmacokinetic modeling and examine its associations with genetic variants in key genes involved in vitamin B(12)-related pathways. METHODS: In a cohort of 104 young healthy Indian adults, functional vitamin B(12) markers including total vitamin B(12) and holotranscobalamin were measured using chemiluminescence immunoassays. Bioavailability was estimated by nonlinear mixed effects modeling of plasma vitamin B(12) time-concentration profiles using a modified 2-compartment model. Genetic associations were analyzed, and polygenic risk scores (PRSs) were computed. RESULTS: The mean measured vitamin B(12) bioavailability was 52% ± 16%, demonstrating significant 4.4-fold variability. A total of 85 single nucleotide polymorphism (SNPs) in/near 14 genes were significantly associated with vitamin B(12) bioavailability, including 5 previously reported SNPs associated with vitamin B(12)-related traits and 80 novel variants from known vitamin B(12) pathway genes. Bioavailability-PRS explained 72% (95% CI: 60%, 81%) of the variance in vitamin B(12) bioavailability in the same cohort and 55% in a 3-fold cross-validation test. At the first quartile threshold, the PRS identified individuals requiring supplementation with a positive predictive value of 0.32. CONCLUSIONS: These findings provide insights into the genetic determinants of vitamin B(12) absorption and homeostasis, emphasizing the potential of using genetic markers to personalize nutritional strategies. This is critical for identifying subgroups susceptible to vitamin B(12) deficiency despite adequate intake, highlighting the need for precision nutrition led by functional measurements in specific populations. This trial was registered in Clinical Trials Registry of India (CTRI) as CTRI/2020/11/029108.
