ESPE Abstracts

Background: States of vitamin D insufficiency are important determinants of rickets, as well as osteoporosis and other common complex disorders like diabetes, cancer, and infectious diseases. Although, serum concentrations of the vitamin D metabolites are primarily driven by vitamin D supply (by diet or cutaneous synthesis), there is emerging evidence to suggest that single nucleotide variants (SNVs) are important genetic determinants.

Objective and hypothesis: The aim of this study was to determine whether a functional SNV in the 24-hydroxylase gene promoter (c.-686A>G in CYP24A1) shows significant association with blood levels of vitamin D metabolites.

Methods: Genomic DNA from 776 inner-city New Haven children aged 6 months to 3 years with different ancestries (African American, Caucasian, and Hispanic) was genotyped for the c.-686A>G SNV. Serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured by RIA. Ancestry was assessed using a validated panel of 108 ancestry informative markers (AIMs) and data from well-characterized African, Native American, and European population samples.

Results: The main outcome measures were significance of associations between the c.-686A>G CYP24A1 SNV and vitamin D metabolites, with modeling to adjust for age, season, vitamin D intake, and other co-variates. Secondarily we examined the strength of these associations in relation to SNV frequency in the three major ancestral groups. Subjects with the variant allele of CYP24A1 SNV (and decreased 24-hydroxylase activity) had a significantly higher mean 1,25(OH)2D (P<0.001), but all variants were found in African Americans who, as a group, had higher mean 1,25(OH)2D (P<0.0001). Since the effect was not significant when the association was AIMs-adjusted for ancestry, we cannot exclude confounding by stratification.

Conclusion: Further studies of the CYP24A1 SNV are warranted, but the 24-hydroxylase polymorphism may be considered as one possible contributor to the increased 1,25(OH)2D that is widely observed in African Americans.