Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
BACKGROUND
Evidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25-hydroxyvitamin D (25(OH)D) and common variations in key vitamin D-related genes with fatal PCa.


METHODS
In a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single-nucleotide polymorphisms (SNPs) in 7 vitamin D-related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor α) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls.


RESULTS
No statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend = .22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002.


CONCLUSIONS
Statistically significant associations were not observed for either 25(OH)D or vitamin D-related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration.
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Irene M
http://orcid.org/0000-0001-5737-9830
IM
Shui
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.|Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.
Alison M
AM
Mondul
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Sara
S
Lindström
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.|Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
Konstantinos K
KK
Tsilidis
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
Ruth C
RC
Travis
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.|Department of Epidemiology, University of Florida, Gainesville, Florida.
Travis
T
Gerke
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
Demetrius
D
Albanes
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Lorelei A
LA
Mucci
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
Edward
E
Giovannucci
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Peter
P
Kraft
D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D054547:National Cancer Institute (U.S.); D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics* / Q000401:mortality; D012307:Risk Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics
D014807:Vitamin D; C104450:25-hydroxyvitamin D
circulating 25-hydroxyvitamin D; fatal prostate cancer; gene-environment interaction; single-nucleotide polymorphisms; vitamin D genes