The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitamer Levels in CSF and Plasma.

Loes Loohuis,Monique Albersen,Roel A Ophoff,Timothy Wu,Nanda M Verhoeven-Duif,Jurjen Luykx,Simone De Jong,Judith Jans

doi:10.3390/genes10010008

Loes Loohuis, Monique Albersen + Show 6 more

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https://doi.org/10.3390/genes10010008

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Abstract

The active form of vitamin B6, pyridoxal phosphate (PLP), is essential for human metabolism. The brain is dependent on vitamin B6 for its neurotransmitter balance. To obtain insight into the genetic determinants of vitamin B6 homeostasis, we conducted a genome-wide association study (GWAS) of the B6 vitamers pyridoxal (PL), PLP and the degradation product of vitamin B6, pyridoxic acid (PA). We collected a unique sample set of cerebrospinal fluid (CSF) and plasma from the same healthy human subjects of Dutch ancestry (n = 493) and included concentrations and ratios in and between these body fluids in our analysis. Based on a multivariate joint analysis of all B6 vitamers and their ratios, we identified a genome-wide significant association at a locus on chromosome 1 containing the ALPL (alkaline phosphatase) gene (minimal p = 7.89 × 10−10, rs1106357, minor allele frequency (MAF) = 0.46), previously associated with vitamin B6 levels in blood. Subjects homozygous for the minor allele showed a 1.4-times-higher ratio between PLP and PL in plasma, and even a 1.6-times-higher ratio between PLP and PL in CSF than subjects homozygous for the major allele. In addition, we observed a suggestive association with the CSF:plasma ratio of PLP on chromosome 15 (minimal p = 7.93 × 10−7, and MAF = 0.06 for rs28789220). Even though this finding is not reaching genome-wide significance, it highlights the potential of our experimental setup for studying transport and metabolism across the blood–CSF barrier. This GWAS of B6 vitamers identifies alkaline phosphatase as a key regulator in human vitamin B6 metabolism in CSF as well as plasma. Furthermore, our results demonstrate the potential of genetic studies of metabolites in plasma and CSF to elucidate biological aspects underlying metabolite generation, transport and degradation.

Highlights

The active form of vitamin B6, pyridoxal phosphate (PLP), functions as a co-factor in >200 enzymatic reactions in human metabolism [1,2]
Multivariate analysis resulted in one genome-wide significant locus on chromosome 1, containing the neuroblastoma breakpoint family member 3 (NBPF3) and ALPL genes (Figure 2, Table 2, Figure 3A), with index SNP rs1106357 (p = 7.89 × 10−10, MAF = 0.46)
Higher PLP:PL ratios in cerebrospinal fluid (CSF) and plasma are caused by higher concentrations of PLP rather than by lower PL: subjects homozygous for the minor allele showed a 1.5-times-higher concentration of PLP in CSF (20.3 vs 13.9 nmol/L) and a 1.4times-higher concentration of PLP in plasma (67.8 vs 48.2 nmol/L) than subjects homozygous for the

Summary

Introduction

The active form of vitamin B6, pyridoxal phosphate (PLP), functions as a co-factor in >200 enzymatic reactions in human metabolism [1,2]. Inverse relationships have been found between vitamin B6 and conditions such as diabetes, oxidative stress, cardiovascular disease, inflammation and cancer [3,4,5,6,7]. Its rolesuch in amino acid oxidative and neurotransmitter metabolism renders vitaminand B6 vitamin. B6 and conditions as diabetes, stress, cardiovascular disease, inflammation foramino brain acid development and functioning. Lower concentrations of PLP in plasma cancer [3,4,5,6,7].essential. Lower concentrations of PLP in plasma have not Inventory [8]), and with poor cognition [9] and(according

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