Genome-wide association study of circulating vitamin D–binding protein1234

• Published in: The American journal of clinical nutrition Vol. 99; no. 6; pp. 1424 - 1431
• Main Authors: Moy, Kristin A, Mondul, Alison M, Zhang, Han, Weinstein, Stephanie J, Wheeler, William, Chung, Charles C, Männistö, Satu, Yu, Kai, Chanock, Stephen J, Albanes, Demetrius
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.06.2014; American Society for Nutrition
• Subjects: Vitamins, Minerals, and Phytochemicals
• ISSN: 0002-9165; 1938-3207
• DOI: 10.3945/ajcn.113.080309

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. We aimed to characterize common genetic variants that influence the DBP biochemical phenotype. 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. 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. 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. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention clinical trial was registered at clinicaltrials.gov as NCT00342992.