Genome-wide association study of circulating vitamin D-binding protein

Abstract

Background: Vitamin D status may influence a spectrum of health outcomes, including osteoporosis, arthritis, cardiovascular disease, and cancer. Vitamin D-binding protein (DBP) is the primary carrier of vitamin D in the circulation and regulates the bioavailability of 25-hydroxyvitamin D. Epidemiologic studies have shown direct DBP-risk relations and modification by DBP of vitamin D-disease associations.

Objective: We aimed to characterize common genetic variants that influence the DBP biochemical phenotype.

Design: We conducted a genome-wide association study (GWAS) of 1380 men through linear regression of single-nucleotide polymorphisms (SNPs) in the Illumina HumanHap500/550/610 array on fasting serum DBP, assuming an additive genetic model, with adjustment for age at blood collection.

Results: We identified 2 independent SNPs located in the gene encoding DBP, GC, that were highly associated with serum DBP: rs7041 (P = 1.42 × 10⁻²⁴⁶) and rs705117 (P = 4.7 × 10⁻⁹¹). For both SNPs, mean serum DBP decreased with increasing copies of the minor allele: mean DBP concentrations (nmol/L) were 7335, 5149, and 3152 for 0, 1, and 2 copies of rs7041 (T), respectively, and 6339, 4280, and 2341, respectively, for rs705117 (G). DBP was also associated with rs12144344 (P = 5.9 × 10⁻⁷) in ST6GALNAC3.

Conclusions: In this GWAS analysis, to our knowledge the first to examine this biochemical phenotype, 2 variants in GC--one exonic and one intronic--were associated with serum DBP concentrations at the genome-wide level of significance. Understanding the genetic contributions to circulating DBP may provide greater insights into the vitamin D binding, transport, and other functions of DBP and the effect of vitamin D status on health outcomes.

Trial registration: ClinicalTrials.gov NCT00342992.

FIGURE 1.

Quantile-quantile plot of the 591,610 single nucleotide polymorphisms from the genome-wide association study scan (n = 1380; λ_GC = 1.0053).

FIGURE 2.

Genome-wide associations of circulating vitamin D–binding protein by chromosome position and –log₁₀ P value from linear regression.

FIGURE 3.

Regional plot of association, recombination hot spots, and linkage disequilibrium for rs7041 and rs705117 on chromosome 4. Association results from a trend test in –log₁₀ (P values) (gray diamonds) of the single nucleotide polymorphisms are shown according to their chromosomal positions. Linkage disequilibrium structure based on the 1000 Genomes Finnish data (n = 93) was visualized by snp.plotter, R software. The line graph shows likelihood ratio statistics for recombination hot spot by SequenceLDhot software based on the background recombination rates inferred by PHASE v2.1 with the use of 1000 Genomes Finnish data. Physical locations are based on National Center for Biotechnology Information human genome build 37. Gene annotation was based on the National Center for Biotechnology Information RefSeq genes from the UCSC Genome Browser.