title: Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers.
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.
authors.affiliation: Department of Pediatrics (Endocrinology), Yale University School of Medicine, New Haven, CT 06520-8064, USA. Thomas.carpenter@yale.edu
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.forename: Jane H
authors.initials: JH
authors.lastname: Zhang
authors.forename: Esteban
authors.initials: E
authors.lastname: Parra
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Ellis
authors.forename: Christine
authors.initials: C
authors.lastname: Simpson
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.forename: Jody
authors.initials: J
authors.lastname: Balko
authors.forename: Lei
authors.initials: L
authors.lastname: Fu
authors.forename: Betty Y-L
authors.initials: BY
authors.lastname: Wong
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
mesh_terms: D000483:Alleles; D002675:Child, Preschool; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood; D014809:Vitamin D-Binding Protein / Q000097:blood* / Q000235:genetics
chemical_list: D005819:Genetic Markers; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D