Vitamin B6 and riboflavin, their metabolic interaction and relationship with MTHFR genotype, in adults aged 18-102 years

Harry Jarrett, H McNulty, Catherine Hughes, K. Pentieva, JJ Strain, Adrian McCann, LB McAnena, C Cunningham, AM Molloy, A Flynn, S. M. Hopkins, Geraldine Horigan, Ciara O'Connor, Janette Walton, Breige McNulty, Mike Gibney, Yvonne Lamers, M Ward

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Abstract

BACKGROUND: The generation of the active form of vitamin B-6, pyridoxal 5'-phosphate (PLP), in tissues is dependent upon riboflavin as flavin mononucleotide, but whether this interaction is important for maintaining vitamin B-6 status is unclear. OBJECTIVE: To investigate vitamin B-6 and riboflavin status, their metabolic interaction, and relationship with methylenetetrahydrofolate reductase (MTHFR) genotype in adulthood. METHODS: Data from 5612 adults aged 18-102 y were drawn from the Irish National Adult Nutrition Survey (NANS; population-based sample) and the Trinity-Ulster Department of Agriculture (TUDA) and Genovit cohorts (volunteer samples). Plasma PLP and erythrocyte glutathione reductase activation coefficient (EGRac), as a functional indicator of riboflavin, were determined. RESULTS: Older (≥65 y) compared with younger (<65 y) adults had significantly lower PLP concentrations (P < 0.001). A stepwise decrease in plasma PLP was observed across riboflavin categories, from optimal (EGRac ≤1.26), to suboptimal (EGRac: 1.27-1.39), to deficient (EGRac ≥1.40) status, an effect most pronounced in older adults (mean ± SEM: 76.4 ± 0.9 vs 65.0 ± 1.1 vs 55.4 ± 1.2 nmol/L; P < 0.001). In individuals with the variant MTHFR 677TT genotype combined with riboflavin deficiency, compared with non-TT (CC/CT) genotype participants with sufficient riboflavin, we observed PLP concentrations of 52.1 ± 2.9 compared with 76.8 ±0.7 nmol/L (P < 0.001). In participants with available dietary data (i.e., NANS cohort, n = 936), PLP was associated with vitamin B-6 intake (nonstandardized regression coefficient β: 2.49; 95% CI 1.75, 3.24; P < 0.001), supplement use (β: 81.72; 95% CI: 66.01, 97.43; P < 0.001), fortified food (β: 12.49; 95% CI: 2.08, 22.91; P = 0.019), and EGRac (β: -65.81; 95% CI: -99.08, -32.54; P < 0.001), along with BMI (β: -1.81; 95% CI: -3.31, -0.30; P = 0.019). CONCLUSIONS: These results are consistent with the known metabolic dependency of PLP on flavin mononucleotide (FMN) and suggest that riboflavin may be the limiting nutrient for maintaining vitamin B-6 status, particularly in individuals with the MTHFR 677TT genotype. Randomized trials are necessary to investigate the PLP response to riboflavin intervention within the dietary range. The TUDA study and the NANS are registered at www.ClinicalTrials.gov as NCT02664584 (27 January 2016) and NCT03374748 (15 December 2017), respectively.Clinical Trial Registry details: Trinity-Ulster-Department of Agriculture (TUDA) study, ClinicalTrials.gov no. NCT02664584 (January 27th 2016); National Adult Nutrition Survey (NANS), ClinicalTrials.gov no. NCT03374748 (December 15th 2017).

Original languageEnglish
Pages (from-to)1767-1778
Number of pages12
JournalThe American Journal of Clinical Nutrition
Volume116
Issue number6
Early online date19 Dec 2022
DOIs
Publication statusPublished (in print/issue) - 10 Feb 2023

Bibliographical note

Funder information:
This study was completed as part of the DERiVE project, awarded under the Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI-HDHL) scheme for transnational research under the “Biomarkers for Nutrition and Health” scheme: UK–Biotechnology and Biological Sciences Research Council (BBSRC, grant ref: BB/P028241/1). The Trinity-Ulster Department of Agriculture (TUDA) and National Adult and Nutrition Survey (NANS) data were collected as part of an All-Ireland initiative under the Joint Irish Nutrigenomics Organisation (JINGO), supported by the Irish Department of Agriculture and Food, and the Marine and Health Research Board [under the Food Institutional Research Measure (FIRM)] and the Northern Ireland Department for Employment and Learning (under its Strengthening the All-Island Research Base initiative). The funders of this research had no role in the design, methods, subject recruitment, data collections, analysis, and preparation of paper. The Northern Ireland Department for the Economy (DfE) provided a PhD studentship for HJ.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Funding Information:
This study was completed as part of the DERiVE project, awarded under the Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI-HDHL) scheme for transnational research under the “Biomarkers for Nutrition and Health” scheme: UK–Biotechnology and Biological Sciences Research Council (BBSRC, grant ref: BB/P028241/1). The Trinity-Ulster Department of Agriculture (TUDA) and National Adult and Nutrition Survey (NANS) data were collected as part of an All-Ireland initiative under the Joint Irish Nutrigenomics Organisation (JINGO), supported by the Irish Department of Agriculture and Food, and the Marine and Health Research Board [under the Food Institutional Research Measure (FIRM)] and the Northern Ireland Department for Employment and Learning (under its Strengthening the All-Island Research Base initiative). The funders of this research had no role in the design, methods, subject recruitment, data collections, analysis, and preparation of paper. The Northern Ireland Department for the Economy (DfE) provided a PhD studentship for HJ.

Funding Information:
The authors’ responsibilities were as follows—MW, HM, HJ, CFH, KP, YL, and JJS: conceptualized and designed the study; MW, HM, KP, CFH, JJS, AMM, CC, AF, JW, YL, and MJG: obtained study funding; CFH, GH, JW, SMH, and BAM: collected the data; LM, AM, HJ, and CO: conducted the laboratory analysis under the guidance of KP; HJ, CC, LM, and CFH: analyzed the data; CC: provided clinical expertise; HJ, MW, HM, CFH, and KP: drafted the original manuscript; JJS, AM, LM, CC, AMM, AF, SMH, GH, CO, JW, BAM, MJG, and YL: provided critical feedback to improve the intellectual content; HM and MW: had primary responsibility for the final content; and all authors: read and approved the final manuscript. Data described in the article, code book, and analytic code will be made available upon request, pending application and approval from the Irish Universities Nutrition Alliance (IUNA) Data Access Committee. This study was completed as part of the DERiVE project, awarded under the Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI-HDHL) scheme for transnational research under the “Biomarkers for Nutrition and Health” scheme: UK–Biotechnology and Biological Sciences Research Council (BBSRC, grant ref: BB/P028241/1). The Trinity-Ulster Department of Agriculture (TUDA) and National Adult and Nutrition Survey (NANS) data were collected as part of an All-Ireland initiative under the Joint Irish Nutrigenomics Organisation (JINGO), supported by the Irish Department of Agriculture and Food, and the Marine and Health Research Board [under the Food Institutional Research Measure (FIRM)] and the Northern Ireland Department for Employment and Learning (under its Strengthening the All-Island Research Base initiative). The funders of this research had no role in the design, methods, subject recruitment, data collections, analysis, and preparation of paper. The Northern Ireland Department for the Economy (DfE) provided a PhD studentship for HJ. Author disclosures: The authors report no conflicts of interest. Supplemental Figure 1 is available from the “Supplementary data” link in the online posting of the article at https://academic.oup.com/ajcn/.

Publisher Copyright:
© 2022 American Society for Nutrition.

Keywords

  • Vitamin B6
  • riboflavin
  • pyridoxal 5’-phosphate
  • erythrocyte glutathione reductase activation coefficient
  • B-vitamin biomarkers
  • MTHFR
  • dietary intakes
  • Trinity-Ulster-Department of Agriculture (TUDA)
  • vitamin B-6
  • pyridoxal 5′-phosphate
  • Trinity-Ulster Department of Agriculture (TUDA)

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