title: 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.
  
  
  METHODS
  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.
authors.affiliation: 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).
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Moy
authors.affiliation: 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).
authors.forename: Alison M
authors.initials: AM
authors.lastname: Mondul
authors.affiliation: 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).
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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).
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Weinstein
authors.affiliation: 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).
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.affiliation: 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).
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chung
authors.affiliation: 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).
authors.forename: Satu
authors.initials: S
authors.lastname: Männistö
authors.affiliation: 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).
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: 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).
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: 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).
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
mesh_terms: D015652:25-Hydroxyvitamin D 2 / Q000097:blood / Q000378:metabolism; D000368:Aged; D000483:Alleles; D002112:Calcifediol / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D005091:Exons; D005387:Finland; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D015652:25-Hydroxyvitamin D 2; D002112:Calcifediol; D017350:N-Acetylgalactosaminyltransferases; D012799:Sialyltransferases; D014809:Vitamin D-Binding Protein; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C098871:Neu5Ac N-acetylgalactosamine 2,6-sialyltransferase
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