The American journal of clinical nutrition · 2025
Novel genetic variants associated with stable isotope-based vitamin B12 bioavailability measurements in healthy Indian adults.
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Sivadas Ambily, Devi Sarita, Pasanna Roshni M, Dutta Ujjaini, Sachdev Harshpal Singh, Kurpad Anura V
Аннотация
BACKGROUND: Vitamin B12 deficiency is a prevalent health concern that can lead to hematological and neurological disorders. Despite adequate intake, vitamin B12 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 B12 concentration, they have not been validated using precise, stable, isotope-based measurements of vitamin B12 bioavailability.
OBJECTIVES: To measure the plasma bioavailability of an oral dose of [13C]-labeled vitamin B12 (cyanocobalamin) using 2-compartment pharmacokinetic modeling and examine its associations with genetic variants in key genes involved in vitamin B12-related pathways.
METHODS: In a cohort of 104 young healthy Indian adults, functional vitamin B12 markers including total vitamin B12 and holotranscobalamin were measured using chemiluminescence immunoassays. Bioavailability was estimated by nonlinear mixed effects modeling of plasma vitamin B12 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 B12 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 B12 bioavailability, including 5 previously reported SNPs associated with vitamin B12-related traits and 80 novel variants from known vitamin B12 pathway genes. Bioavailability-PRS explained 72% (95% CI: 60%, 81%) of the variance in vitamin B12 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 B12 absorption and homeostasis, emphasizing the potential of using genetic markers to personalize nutritional strategies. This is critical for identifying subgroups susceptible to vitamin B12 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.
OBJECTIVES: To measure the plasma bioavailability of an oral dose of [13C]-labeled vitamin B12 (cyanocobalamin) using 2-compartment pharmacokinetic modeling and examine its associations with genetic variants in key genes involved in vitamin B12-related pathways.
METHODS: In a cohort of 104 young healthy Indian adults, functional vitamin B12 markers including total vitamin B12 and holotranscobalamin were measured using chemiluminescence immunoassays. Bioavailability was estimated by nonlinear mixed effects modeling of plasma vitamin B12 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 B12 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 B12 bioavailability, including 5 previously reported SNPs associated with vitamin B12-related traits and 80 novel variants from known vitamin B12 pathway genes. Bioavailability-PRS explained 72% (95% CI: 60%, 81%) of the variance in vitamin B12 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 B12 absorption and homeostasis, emphasizing the potential of using genetic markers to personalize nutritional strategies. This is critical for identifying subgroups susceptible to vitamin B12 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.