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Vitamin D Genes & Exposure in Relation to Kidney Cancer Open Access

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Introduction: Vitamin D may have anti-carcinogenic properties that include inhibition of clonal tumor cell proliferation, induction of immune cell differentiation, and decreased angiogenesis. Within the kidney, vitamin D is metabolized to its active form. Since the incidence of renal cell carcinoma (RCC) and prevalence of vitamin D deficiency have increased over the past few decades, this study hypothesized that increased vitamin D exposure (via occupational ultraviolet exposure or dietary intake) was associated with decreased RCC risk and that genetic variations within the vitamin D pathway modified risk. Methods: Cases (N=1,097) and controls (N=1,476) in a hospital-based case-control study in Central Europe were interviewed to collect data on demographics and lifetime occupational histories. Genomic DNA was also collected from a subset of participants. Results: Significant reduction in RCC risk was observed with occupational ultraviolet exposure among male participants. No association between ultraviolet exposure and RCC risk was observed among females. Analyses stratified by latitude showed a stronger reduction in risk among males at the highest latitude study site, Russia. Analyses of eight vitamin D pathway genes revealed significant associations between RCC risk and the vitamin D receptor (VDR) and retinoid-X-receptor-alpha (RXRA) genes. Across VDR, three haplotypes within two regions were associated with increased risk. Across RXRA, RCC risk was higher among participants with one particular haplotype located downstream of the coding region. Dietary analyses showed increased RCC risk with increasing intake frequency of yogurt for foods rich in calcium, while decreased risk was observed with eggs for foods rich in vitamin D. Additional evaluation of RXRA and VDR, revealed RXRA variants, 3‘ of the coding sequence, modified associations between RCC risk and intake frequency of vitamin D rich foods, specifically eggs. Conversely, RXRA variants in introns 1 and 4 modified associations between calcium rich foods. Furthermore, increased RCC risk was observed with increasing occupational ultraviolet exposure among males with one specific VDR haplotype, centered on intron two. Conclusion: Results suggest that vitamin D is associated with RCC risk. Genetic variants across VDR and RXRA genes may be associated with RCC risk and may modify associations between RCC risk and vitamin D.

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