Common Variants at Putative Regulatory Sites of the Tissue Nonspecific Alkaline Phosphatase Gene Influence Circulating Pyridoxal 5'-Phosphate Concentration in Healthy Adults

Abstract

Background: Vitamin B-6 interconversion enzymes are important for supplying pyridoxal 5'-phosphate (PLP), the co-enzyme form, to tissues. Variants in the genes for these enzymes [tissue nonspecific alkaline phosphatase (ALPL), pyridoxamine 5'-phosphate oxidase, pyridoxal kinase, and pyridoxal phosphatase] could affect enzyme function and vitamin B-6 status.

Objectives: We tested whether single-nucleotide polymorphisms (SNPs) in these genes influence vitamin B-6 status markers [plasma PLP, pyridoxal (PL), and 4-pyridoxic acid (PA)], and explored potential functional effects of the SNPs.

Methods: Study subjects were young, healthy adults from Ireland (n = 2345). We measured plasma PLP, PL, and PA with liquid chromatography-tandem mass spectrometry and genotyped 66 tag SNPs in the 4 genes. We tested for associations with single SNPs in candidate genes and also performed genome-wide association study (GWAS) and gene-based analyses.

Results: Seventeen SNPs in ALPL were associated with altered plasma PLP in candidate gene analyses (P < 1.89 × 10(-4)). In the GWAS, 5 additional ALPL SNPs were associated with altered plasma PLP (P < 5.0 × 10(-8)). Gene-based analyses that used the functional linear model β-spline (P = 4.04 × 10(-15)) and Fourier spline (P = 5.87 × 10(-15)) methods also showed associations between ALPL and altered plasma PLP. No SNPs in other genes were associated with plasma PLP. The association of the minor CC genotype of 1 ALPL SNP, rs1256341, with reduced ALPL expression in the HapMap Northern European ancestry population is consistent with the positive association between the CC genotype and plasma PLP in our study (P = 0.008). No SNP was associated with altered plasma PL or PA.

Conclusions: In healthy adults, common variants in ALPL influence plasma PLP concentration, the most frequently used biomarker for vitamin B-6 status. Whether these associations are indicative of functional changes in vitamin B-6 status requires more investigation.

Keywords: alkaline phosphatase; dietary supplements; pyridoxal; pyridoxal phosphate; pyridoxic acid; vitamin B-6.