Kristin A Moy1, Alison M Mondul1, Han Zhang1, Stephanie J Weinstein1, William Wheeler1, Charles C Chung1, Satu Männistö1, Kai Yu1, Stephen J Chanock1, Demetrius Albanes1. 1. From the Nutritional Epidemiology Branch (KAM, AMM, SJW, and DA), Biostatistics Branch (HZ and KY), Cancer Genomics Research Laboratory (CCC), and Office of the Director (SJC), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; Information Management Services Inc, Silver Spring, MD (WW); and the Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland (SM).
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.
RCT Entities:
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.
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