title: Joint effects of colorectal cancer susceptibility loci, circulating 25-hydroxyvitamin D and risk of colorectal cancer.
abstract: BACKGROUND
  Genome wide association studies (GWAS) have identified several SNPs associated with colorectal cancer (CRC) susceptibility. Vitamin D is also inversely associated with CRC risk.
  
  
  METHODS
  We examined main and joint effects of previously GWAS identified genetic markers of CRC and plasma 25-hydroxyvitamin D (25(OH)D) on CRC risk in three prospective cohorts: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Physicians' Health Study (PHS). We included 1895 CRC cases and 2806 controls with genomic DNA. We calculated odds ratios and 95% confidence intervals for CRC associated with additive genetic risk scores (GRSs) comprised of all CRC SNPs and subsets of these SNPs based on proximity to regions of increased vitamin D receptor binding to vitamin D response elements (VDREs), based on published ChiP-seq data. Among a subset of subjects with additional prediagnostic 25(OH)D we tested multiplicative interactions between plasma 25(OH)D and GRS's. We used fixed effects models to meta-analyze the three cohorts.
  
  
  RESULTS
  The per allele multivariate OR was 1.12 (95% CI, 1.06-1.19) for GRS-proximalVDRE; and 1.10 (95% CI, 1.06-1.14) for GRS-nonproxVDRE. The lowest quartile of plasma 25(OH)D compared with the highest, had a multivariate OR of 0.63 (95% CI, 0.48-0.82) for CRC. We did not observe any significant interactions between any GRSs and plasma 25(OH)D.
  
  
  CONCLUSIONS
  We did not observe evidence for the modification of genetic susceptibility for CRC according to vitamin D status, or evidence that the effect of common CRC risk alleles differed according to their proximity to putative VDR binding sites.
authors.affiliation: Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Hiraki
authors.affiliation: Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Joshi
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Kimmie
authors.initials: K
authors.lastname: Ng
authors.affiliation: Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Aditi
authors.initials: A
authors.lastname: Hazra
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood* / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D