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.
Carcinogenesis (Impact Factor: 5.33). 04/2009; 30(5):769-76. DOI: 10.1093/carcin/bgp055
Source: PubMed


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.

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Available from: Neal Freedman
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    • "Most circulating vitamin D metabolites are bound to DBP to be transported to target organs. In the previous candidate gene studies and the recent GWAS, some GC polymorphisms were associated with serum 25(OH)D concentration, and the strongest association was observed for rs2282679 [19,20,26]. Our results provide supportive evidence that serum 25(OH)D concentration might partly be affected by a polymorphism of rs2282679 or the other variants that are in tight linkage disequilibrium with rs2282679. "
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    ABSTRACT: Vitamin D deficiency has been reported to be common in patients with rheumatoid arthritis (RA) who have a higher prevalence of osteoporosis and hip fracture than healthy individuals. Genetic variants affecting serum 25-hydroxyvitamin D (25(OH)D) concentration, an indicator of vitamin D status, were recently identified by genome-wide association studies of Caucasian populations. The purpose of this study was to validate the association and to test whether the serum 25(OH)D linked genetic variants were associated with the occurrence of hip fracture in Japanese RA patients. DNA samples of 1,957 Japanese RA patients were obtained from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort DNA collection. First, five single nucleotide polymorphisms (SNPs) that were reported to be associated with serum 25(OH)D concentration by genome-wide association studies were genotyped. The SNPs that showed a significant association with serum 25(OH)D level in the cross-sectional study were used in the longitudinal analysis of hip fracture risk. The genetic risk for hip fracture was determined by a multivariate Cox proportional hazards model in 1,957 patients with a maximum follow-up of 10 years (median, 8 years). Multivariate linear regression analyses showed that rs2282679 in GC (the gene encoding group-specific component (vitamin D binding protein)) locus was significantly associated with lower serum 25(OH)D concentration (P = 8.1 X 10-5). A Cox proportional hazards model indicated that rs2282679 in GC was significantly associated with the occurrence of hip fracture in a recessive model (hazard ratio (95% confidence interval) = 2.52 (1.05-6.05), P = 0.039). A two-staged analysis demonstrated that rs2282679 in GC was associated with serum 25(OH)D concentration and could be a risk factor for hip fracture in Japanese RA patients.
    Full-text · Article · Mar 2014 · Arthritis research & therapy
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    • "GC, also known as vitamin D-binding protein (DBP), and it is a member of the albumin family [23], encodes DBP synthesized in the liver and transports vitamin D and its metabolites. Recently, studies investigated the association between GC polymorphisms and 25(OH)D status [24-28]. Because certain mutations in the GC gene are known to cause defects in GC function, we hypothesized that GC polymorphisms can predict susceptibility to developing rickets. "
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    ABSTRACT: Vitamin D deficiency rickets is common in China. Genetic factors may play an important role in the susceptibility to rickets. Our study aimed to identify the relationship between three vitamin D-related genes (group specific component [GC], cytochrome P450, family 2, subfamily R, polypeptide 1 (CYP2R1), and 7-dehydrocholesterol reductase/nicotinamide-adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) and rickets in Han Chinese children from northeastern China. A total of 506 Han children from northeastern China were enrolled in the current study. Twelve SNPs in three candidate genes were genotyped using the SNaPshot assay. Linear regression was used to examine the effect of 12 single-nucleotide polymorphisms (SNPs) on the risk of rickets. In our case--control cohort, six alleles of the 12 SNPs conferred a significantly increased risk of rickets in GC (rs4588 C, P = 0.003, OR: 0.583, 95% CI: 0.412-0.836; rs222020 C, P = 0.009, OR: 1.526, 95% CI:1.117-2.0985; rs2282679 A, P = 0.010, OR: 0.636, 95% CI :0.449-0.900; and rs2298849 C, P = 0.001, OR: 1.709, 95% CI:1.250-2.338) and in CYP2R1 (rs10741657 G, P = 0.019, OR: 1.467, 95% CI:1.070-2.011; and rs2060793 G, P = 0.023, OR: 0.689, 95% CI:0.502-0.944). The results remained significant after adjustment for sex and body mass index. We further analyzed the effect of genotypes under three different genetic models. After using Bonferroni's method for multiple corrections, rs4588, rs2282679, and rs2298849 of the GC gene were significantly associated with rickets under the dominant (P =0.003 for rs4588, P =0.024 for rs2282679, and P =0.005 for rs2298849) and additive models (P = 0.006 for rs4588, P = 0.024 for rs2282679, and P = 0.005 for rs2298849). Haplotype analysis showed that the CAT haplotype of the GC gene (P = 0.005) and the GAA haplotype of the CYP2R1 gene (P = 0.026) were associated with susceptibility to rickets. This case--control study confirmed the strong effect of GC and CYP2R1 loci on rickets in Han children from northeastern China.
    Full-text · Article · Sep 2013 · BMC Medical Genetics
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    • "Higher 25(OH)D levels are associated with a lower risk of incident left-sided colorectal adenomas [135]. Multiple meta-analyses , and large prospective and retrospective observational studies have established that vitamin D deficiency is associated with an increased risk of colon [136] [137] [138] [139], breast [140] [141] [142], and prostate cancer [143] [144]. Furthermore, increased sunlight exposure is associated with a reduced risk of non-Hodgkin's lymphoma [145] and VDR polymorphisms are associated with adenocarcinoma in the colon [146], ovary [147], breast, prostate, renal cell carcinoma, and melanoma [148]. "
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    ABSTRACT: Vitamin D is synthesized predominantly in the liver and functions as an important secosteroid hormone with pleiotropic effects. While its key regulatory role in calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D also regulates cell proliferation and differentiation, and has immunomodulatory, anti-inflammatory and anti-fibrotic properties. These non-skeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C. Small studies suggest that vitamin D supplementation improves sustained viral response rates, while 1α-hydroxylase polymorphisms and vitamin D-binding protein are also implicated in therapeutic outcomes. Vitamin D deficiency also closely relates to the severity of non-alcoholic fatty liver disease (NAFLD) and is implicated in the pathogenesis of insulin resistance, a key factor in the development of NAFLD. In preclinical studies, phototherapy and vitamin D supplementation ameliorate NAFLD histopathology, while vitamin D is a powerful anti-fibrotic against thioacetamide liver injury. In liver transplant recipients severe vitamin D deficiency predicts, and vitamin D supplementation prevents, acute cellular rejection. The role of vitamin D in the activation and regulation of both innate and adaptive immune systems may explain its importance in the above liver diseases. Further prospective studies are therefore warranted to investigate the therapeutic impact of vitamin D supplementation in chronic liver disease.
    Full-text · Article · May 2012 · Journal of Hepatology
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