Serum parathyroid hormone is related to genetic variation in vitamin D binding protein with respect to total, free, and bioavailable 25-hydroxyvitamin D in middle-aged Caucasians – a cross-sectional study

Abstract

Vitamin D binding protein (DBP) binds vitamin D and its plasma metabolites, including 25-hydroxyvitamin D (25(OH)D), in the circulation. Only a small fraction circulates free (free 25(OH)D). Genetic variation of the GC gene, encoding DBP, has been associated with 25(OH)D concentrations. The roles of DBP and free 25(OH)D concentrations in the biological actions of vitamin D remain unclear. We assessed the relationship between GC gene variants rs4588, rs7041, and rs705124, and serum total 25(OH)D, free and bioavailable 25(OH)D, and serum DBP and parathyroid hormone (PTH) concentrations in 622 Caucasian females (421) and males (201) aged 37–47 years. Concentrations of 25(OH)D, DBP, and PTH were measured from fasting blood samples. Dietary intakes of vitamin D and Ca were evaluated using 1-month food use frequency data, which were collected by a validated Food Frequency Questionnaire on vitamin D and calcium intakes. The subjects filled in the questionnaire covering overall health, medications, use of vitamin D and calcium supplements, and holidays in sunny locations. Three SNPs in the GC gene were genotyped: rs4588, rs7041, and rs705124. The SNPs rs4588 and rs7041 combine to form six common diplotypes. Free and bioavailable 25(OH)D were calculated by using specific binding coefficients. Differences among the diplo- and haplotypes of the GC gene in measures of 25(OH)D, DBP, and PTH were tested by analysis of covariance (ANCOVA) using appropriate covariates. We found significant variation among the SNPs rs4588 and rs7041 variants in DBP, total, free, and bioavailable 25(OH)D, and PTH. DBP concentration was lowest in genotype GC2/2 in both diplotypes and haplotypes (p = 0.039 and 0.039, respectively). The lowest 25(OH)D concentrations were found in diplotype variants GC1S/2, GC1S/F, and GC2/2 (p = 0.033), but free and bioavailable 25(OH)D concentrations were highest in the GC2/2 variant after corrected with a genotype-specific binding coefficient (p < 0.001 in both groups). Surprisingly, one of the lowest PTH concentrations was also present in variant GC2/2 in diplotypes (p = 0.040 of the overall ANCOVA analysis of PTH). Among SNP rs705124, there was a difference only in PTH concentrations (p = 0.013). Our findings indicate that genetic variation of the DBP coding gene, and free concentrations of 25(OH)D may be relevant when vitamin D status, metabolism, and action are investigated.