title: Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case-control study.
abstract: OBJECTIVE
  Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer.
  
  
  METHODS
  In a nested case-control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1-T2/T3-T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism.
  
  
  RESULTS
  We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure.
  
  
  CONCLUSIONS
  We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK. becky.gilbert@bristol.ac.uk.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gilbert
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Carolina
authors.initials: C
authors.lastname: Bonilla
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Metcalfe
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.affiliation: Nuffield Department of Surgery, University of Oxford, Oxford, UK.
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
authors.forename: J Athene
authors.initials: JA
authors.lastname: Lane
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Commissariat à l'Energie Atomique, Center National de Génotypage, Evry, France.|Génome Québec Innovation Centre, McGill University, Montreal, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.|Bristol Biomedical Research Unit in Nutrition, National Institute for Health Research, Bristol, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000368:Aged; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics; D002117:Calcitriol / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D059647:Gene-Environment Interaction; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics*; D012306:Risk; D018570:Risk Assessment; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D014809:Vitamin D-Binding Protein / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human; D017430:Prostate-Specific Antigen; D002117:Calcitriol