title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Center for Human Genetics, Marshfield Clinic, Marshfield, WI;
authors.forename: Tonia C
authors.initials: TC
authors.lastname: Carter
authors.affiliation: National Human Genome Research Institute.
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.affiliation: Institute of Molecular Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland;
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD;
authors.forename: Ruzong
authors.initials: R
authors.lastname: Fan
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD;
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA;
authors.forename: Barry
authors.initials: B
authors.lastname: Shane
authors.affiliation: UCD Institute of Food and Health, University College Dublin, Dublin, Ireland;
authors.forename: Eileen R
authors.initials: ER
authors.lastname: Gibney
authors.affiliation: Bevital AS, Bergen, Norway; and.
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Midttun
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: National Human Genome Research Institute.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Cropp
authors.affiliation: National Human Genome Research Institute.
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.affiliation: National Human Genome Research Institute.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.affiliation: National Human Genome Research Institute.
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: National Human Genome Research Institute.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD; jamesmills@nih.gov.
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood / Q000235:genetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002853:Chromatography, Liquid; D005260:Female; D055106:Genome-Wide Association Study; D064368:Healthy Volunteers; D006801:Humans; D007494:Ireland; D016014:Linear Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011730:Pyridoxal / Q000097:blood; D011732:Pyridoxal Phosphate / Q000097:blood*; D011735:Pyridoxic Acid / Q000097:blood; D053719:Tandem Mass Spectrometry; D025101:Vitamin B 6 / Q000097:blood; D055815:Young Adult
chemical_list: D015415:Biomarkers; D011730:Pyridoxal; D011735:Pyridoxic Acid; D011732:Pyridoxal Phosphate; D025101:Vitamin B 6; D001219:Aspartate Aminotransferases; C548267:ALPL protein, human; D000469:Alkaline Phosphatase
keywords: alkaline phosphatase; dietary supplements; pyridoxal; pyridoxal phosphate; pyridoxic acid; vitamin B-6