Arve Ulvik1, Øivind Midttun1, Adrian McCann1, Klaus Meyer1, Grethe Tell2, Ottar Nygård3, Per M Ueland4. 1. Bevital, Bergen, Norway. 2. Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. 3. Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. 4. Department of Clinical Science, University of Bergen, Bergen, Norway.
Abstract
BACKGROUND:Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. OBJECTIVE: This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts. METHODS: We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods. RESULTS:3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3'-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < ∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age. CONCLUSIONS: The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.
RCT Entities:
BACKGROUND:Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. OBJECTIVE: This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts. METHODS: We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods. RESULTS:3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3'-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < ∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age. CONCLUSIONS: The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.
Authors: Andreana N Holowatyj; Jennifer Ose; Biljana Gigic; Tengda Lin; Arve Ulvik; Anne J M R Geijsen; Stefanie Brezina; Rama Kiblawi; Eline H van Roekel; Andreas Baierl; Jürgen Böhm; Martijn J L Bours; Hermann Brenner; Stéphanie O Breukink; Jenny Chang-Claude; Johannes H W de Wilt; William M Grady; Thomas Grünberger; Tanja Gumpenberger; Esther Herpel; Michael Hoffmeister; Eric T P Keulen; Dieuwertje E Kok; Janna L Koole; Katharina Kosma; Ewout A Kouwenhoven; Gry Kvalheim; Christopher I Li; Peter Schirmacher; Petra Schrotz-King; Marie C Singer; Fränzel J B van Duijnhoven; Henk K van Halteren; Kathy Vickers; F Jeroen Vogelaar; Christy A Warby; Evertine Wesselink; Per M Ueland; Alexis B Ulrich; Martin Schneider; Nina Habermann; Ellen Kampman; Matty P Weijenberg; Andrea Gsur; Cornelia M Ulrich Journal: Am J Clin Nutr Date: 2022-08-04 Impact factor: 8.472
Authors: Janna L Koole; Martijn J L Bours; Anne J M R Geijsen; Biljana Gigic; Arve Ulvik; Dieuwertje E Kok; Stefanie Brezina; Jennifer Ose; Andreas Baierl; Jürgen Böhm; Hermann Brenner; Stéphanie O Breukink; Jenny Chang-Claude; Fränzel J B van Duijnhoven; Peter van Duijvendijk; Tanja Gumpenberger; Nina Habermann; Henk K van Halteren; Michael Hoffmeister; Andreana N Holowatyj; Maryska L G Janssen-Heijnen; Eric T P Keulen; Rama Kiblawi; Flip M Kruyt; Christopher I Li; Tengda Lin; Øivind Midttun; Anita R Peoples; Eline H van Roekel; Martin A Schneider; Petra Schrotz-King; Alexis B Ulrich; Kathy Vickers; Evertine Wesselink; Johannes H W de Wilt; Andrea Gsur; Per M Ueland; Cornelia M Ulrich; Ellen Kampman; Matty P Weijenberg Journal: Am J Clin Nutr Date: 2021-06-01 Impact factor: 7.045
Authors: Joanna L Clasen; Alicia K Heath; Heleen Van Puyvelde; Inge Huybrechts; Jin Young Park; Pietro Ferrari; Mattias Johansson; Ghislaine Scelo; Arve Ulvik; Øivind Midttun; Per Magne Ueland; Christina C Dahm; Jytte Halkjær; Anja Olsen; Theron Johnson; Verena Katzke; Matthias B Schulze; Giovanna Masala; Francesco Segrado; Maria Santucci de Magistris; Carlotta Sacerdote; Marga C Ocké; Leila Luján-Barroso; Ana Ching-López; José María Huerta; Eva Ardanaz; Pilar Amiano; Ulrika Ericson; Jonas Manjer; Björn Gylling; Ingegerd Johansson; Julie Schmidt; Elisabete Weiderpass; Elio Riboli; Amanda J Cross; David C Muller Journal: Am J Clin Nutr Date: 2021-07-01 Impact factor: 7.045