Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers

Authors

  • Thomas O Carpenter,

    Corresponding author
    1. Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
    2. Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
    • Yale University School of Medicine, Department of Pediatrics (Endocrinology), P.O. Box 208064, 333 Cedar St., New Haven, CT 06520-8064, USA.
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  • Jane H Zhang,

    1. Veterans Administration Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven, CT, USA
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  • Esteban Parra,

    1. Department of Anthropology, University of Toronto at Mississauga, Ontario, Canada
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  • Bruce K Ellis,

    1. Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
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  • Christine Simpson,

    1. Department of Internal Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
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  • William M Lee,

    1. Department of Internal Medicine (Digestive and Liver Diseases), University of Texas–Southwestern Medical School, Dallas, TX, USA
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  • Jody Balko,

    1. Department of Internal Medicine (Digestive and Liver Diseases), University of Texas–Southwestern Medical School, Dallas, TX, USA
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  • Lei Fu,

    1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    3. Department of Genetics, University of Toronto, Toronto, Ontario, Canada
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  • Betty Y-L Wong,

    1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    3. Department of Genetics, University of Toronto, Toronto, Ontario, Canada
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  • David EC Cole

    1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    3. Department of Genetics, University of Toronto, Toronto, Ontario, Canada
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Abstract

Circulating 25-hydroxyvitamin D (25-OHD) levels vary among human populations. Only limited information regarding determinants of these measures is available for infants and children, particularly in minority groups at greatest risk for vitamin D deficiency. We identified demographic determinants of circulating 25-OHD in a large cohort of minority children, and now extend our studies to examine potential roles of vitamin D binding protein (DBP) as a determinant of 25-OHD levels. Serum DBP level and common single nucleotide polymorphisms (SNPs) at positions 432 and 436 in the GC gene, encoding DBP, were examined. We confirmed self-reported ancestry using ancestry informative markers (AIMs), and included quantitative AIMs scores in the analysis. The multivariate model incorporated previously identified demographic and nutritional determinants of 25-OHD in this cohort, as well as GC SNPs and circulating DBP. Genetic variants in GC differed by self-reported ancestry. The 1f allele (D432/T436) was enriched in African Americans, occurring in 71%. Homozygosity for the 1f allele (DDTT) occurred in 53% of African Americans but only 6% of Caucasians and 13% of Hispanics. Circulating DBP was significantly correlated with 25-OHD. GC SNPs were associated with both circulating DBP and 25-OHD. It appears that progressive substitution of lysine for threonine at the 436 position results in lower circulating 25-OHD. Multivariate analysis revealed that genetic variance in GC significantly contributes to circulating DBP as well as 25-OHD. Moreover, the effect of GC SNPs on 25-OHD are evident after adjusting for their effects on circulating DBP. Thus in young children genetic variance of the common GC T436K SNP affects circulating levels of the DBP protein, which in turn affects circulating 25-OHD. However, the GC genotype also affects circulating 25-OHD independently of its effect on circulating DBP. These findings provide data that may be important in the interpretation of vitamin D status in children of varying ancestral backgrounds. © 2013 American Society for Bone and Mineral Research

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