title: Evidence of differential effects of vitamin d receptor variants on epithelial ovarian cancer risk by predicted vitamin d status.
abstract: BACKGROUND
  Experimental studies suggest vitamin D inhibits ovarian carcinogenesis. Yet, epidemiologic studies of ovarian cancer risk and lifestyle correlates of vitamin D status, plasma 25-hydroxyvitamin D [25(OH)D], or vitamin D receptor (VDR) variants have been inconsistent.
  
  
  OBJECTIVE
  To evaluate VDR genetic associations by high vs. low predicted 25(OH)D, scores derived from known determinants of plasma 25(OH)D. To assess ovarian cancer associations with variants identified in genome-wide association studies (GWAS) of plasma 25(OH)D.
  
  
  METHODS
  We genotyped up to seven VDR and eight 25(OH)D GWAS variants in the Nurses' Health Studies (562 cases, 1,553 controls) and New England Case-Control study (1,821 cases, 1,870 controls). We estimated haplotype scores using expectation-maximization-based algorithms. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CI). We combined study results using DerSimonian and Laird meta-analysis.
  
  
  RESULTS
  Ovarian cancer risk increased per A allele of rs7975232 (VDR; OR = 1.12, 95% CI = 1.01-1.25) among all women. When stratified by predicted 25(OH)D, ovarian cancer was associated with rs731236 (VDR; per C allele OR = 1.31) and rs7975232 (OR = 1.38) among women with high predicted 25(OH)D, but not among women with low levels (P ≤ 0.009). We also observed heterogeneity by predicted 25(OH)D for the ovarian cancer association with VDR 3' end haplotypes (P = 0.009). Of 25(OH)D-associated GWAS loci, rs7041 was associated with reduced ovarian cancer risk (per T allele OR = 0.92, 95% CI = 0.85-0.99), which did not differ by predicted 25(OH)D status.
  
  
  CONCLUSIONS
  Our study suggests an influence of VDR 3' end variants on ovarian cancer risk may be observed in women with high predicted 25(OH)D, which remained even after taking multiple comparisons into consideration. Future studies are needed to confirm our results and explore further the relation between vitamin D exposure, genetic variants, and ovarian cancer risk.
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, MA , USA ; Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Prescott
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, MA , USA ; Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bertrand
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , USA.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Reid
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Permuth-Wey
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, MA , USA ; Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA ; Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA.
authors.forename: Immaculata
authors.initials: I
authors.lastname: De Vivo
authors.affiliation: Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA ; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School , Boston, MA , USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Cramer
authors.affiliation: Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA ; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School , Boston, MA , USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Terry
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, MA , USA ; Department of Epidemiology, Harvard School of Public Health , Boston, MA , USA.
authors.forename: Shelley S
authors.initials: SS
authors.lastname: Tworoger
keywords: haplotype; heterogeneity; ovarian cancer; polymorphism; vitamin D