Carcinogenesis Advance Access originally published online on March 2, 2009
Carcinogenesis 2009 30(5):769-776; doi:10.1093/carcin/bgp055
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Published by Oxford University Press 2009.
Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Bethesda, MD 20892, USA
1 Cancer Prevention Program, Fred Hutchinson Cancer Research Center
2 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98109, USA
3 Division of Urologic Surgery, Washington University School of Medicine, St Louis, MO 63110, USA
4 Anschutz Cancer Pavilion University of Colorado, MS 710, Aurora, CO 80014, USA
5 Present address: Division of Epidemiology, New York University Langone Medical Center, 650 First Ave, New York, NY 10016
* To whom correspondence should be addressed. Tel: +1 301 451 9581; Fax: +1 301 496 6829; Email: ahnj{at}mail.nih.gov
We systematically investigated the association of 48 SNPS in four vitamin D metabolizing genes [CYP27A1, GC, CYP27B1 and CYP24A1] with serum 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels and the association of these SNPS and an additional 164 SNPS in eight downstream mediators of vitamin D signaling [VDR, RXRA, RXRB, PPAR, NCOA1, NCOA2, NCOA3 and SMAD3] with prostate cancer risk in the 749 incident prostate cancer cases and 781 controls of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. 25(OH)D (all cases and controls) and 1,25(OH)2D (a subset of 150 controls) levels were measured by radioimmunoassay and SNP data were genotyped as part of a genome-wide scan. Among investigated SNPS, only four tag SNPS in GC, the major serum 25(OH)D carrier, were associated with 25(OH)D levels; no SNPS were associated with 1,25(OH)2D levels. None of the 212 SNPS examined were associated with cancer risk overall. Among men in the lowest tertile of serum 25(OH)D (<48.9 nmol/l), however, prostate cancer risk was related to tag SNPS in or near the 3' untranslated region (UTR) of VDR, with the strongest association for rs11574143 [odds ratio (95% confidence interval) for risk allele carriers versus wild-type: 2.49 (1.51–4.11), P = 0.0007]; the genotype associations were null among men in tertile 2 and tertile 3. Results from the most comprehensive evaluation of serum vitamin D and its related genes to date suggest that tag SNPS in the 3' UTR of VDR may be associated with risk of prostate cancer in men with low vitamin D status.
Abbreviations: CGEMS, Cancer Genetic Markers of Susceptibility; CYP24A1, cytochrome P450, family 24, subfamily A, polypeptide 1; CYP27A1, cytochrome P450, family 27, subfamily A, polypeptide 1; CYP27B1, cytochrome P450, family 27, subfamily B, polypeptide 1; FDR, false discovery rate; GC, group-specific component; LD, linkage disequilibrium; NCOA1, nuclear receptor coactivator 1; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D; OR, odds ratio; PLCO, Prostate, Lung, Colorectal and Ovarian; RFLP, restriction fragment length polymorphism; RXRA, retinoid X receptor, alpha; RXRB, retinoid X receptor, beta; UTR, untranslated region; VDR, vitamin D (1,25-dihydroxyvitamin D3) receptor
Received December 31, 2008; revised February 14, 2009; accepted February 18, 2009.
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