Genetic variation in the vitamin d pathway in relation to risk of prostate cancer--results from the breast and prostate cancer cohort consortium.

Abstract

BACKGROUND:

Studies suggest that vitamin D status may be associated with prostate cancer risk although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D [25(OH)D] status. We examined prostate cancer risk in relation to single-nucleotide polymorphisms (SNP) in four genes shown to predict circulating levels of 25(OH)D.

METHODS:

SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.

RESULTS:

We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D [per A allele, OR, 0.86; 95% confidence interval (CI), 0.80-0.93; Ptrend = 0.0002) but an increased risk for nonaggressive disease (per A allele: OR, 1.10; 95% CI, 1.04-1.17; Ptrend = 0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6-8 vs. 0-1 alleles, 0.66; 95% CI, 0.44-0.98; Ptrend = 0.003).

CONCLUSIONS:

In this large, pooled analysis, genetic variants related to lower 25(OH)D levels were associated with a decreased risk of aggressive prostate cancer.

IMPACT:

Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.

• Authors: Alison M Mondul, Irene M Shui, Kai Yu, Ruth C Travis, Victoria L Stevens, Daniele Campa, Frederick R Schumacher, Regina G Ziegler, H Bas Bueno-de-Mesquita, Sonja Berndt, E D Crawford, Susan M Gapstur, J Michael Gaziano, Edward Giovannucci, Christopher A Haiman, Brian E Henderson, David J Hunter, Mattias Johansson, Timothy J Key, Loïc Le Marchand, Sara Lindström, Marjorie L McCullough, Carmen Navarro, Kim Overvad, Domenico Palli, Mark Purdue, Meir J Stampfer, Stephanie J Weinstein, Walter C Willett, Meredith Yeager, Stephen J Chanock, Dimitrios Trichopoulos, Laurence N Kolonel, Peter Kraft, Demetrius Albanes
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 22 Issue 4 Pg. 688-96 (Apr 2013) ISSN: 1538-7755 [Electronic] United States
• PMID: 23377224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers, Tumor
• Vitamin D
• Steroid Hydroxylases
• Cytochrome P450 Family 2
• CYP2R1 protein, human
• Cholestanetriol 26-Monooxygenase
• CYP24A1 protein, human
• Vitamin D3 24-Hydroxylase
• Oxidoreductases Acting on CH-CH Group Donors
• 7-dehydrocholesterol reductase

Topics

• Aged
• Biomarkers, Tumor (blood, genetics)
• Case-Control Studies
• Cholestanetriol 26-Monooxygenase (blood, genetics)
• Cytochrome P450 Family 2
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Male
• Neoplasm Grading
• Neoplasm Staging
• Oxidoreductases Acting on CH-CH Group Donors (blood, genetics)
• Polymorphism, Single Nucleotide (genetics)
• Prognosis
• Prospective Studies
• Prostatic Neoplasms (blood, etiology)
• Risk Factors
• Steroid Hydroxylases (blood, genetics)
• Vitamin D (blood)
• Vitamin D3 24-Hydroxylase