Abstract A49: Meta-analysis of vitamin D-binding protein and cancer risk

Abstract

Abstract Antiproliferative effects of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, are well established in various cell types, including normal and malignant cells, by influencing cell differentiation, cell growth and apoptosis. In addition meta-analyses of epidemiological studies showed that serum 25-hydroxyvitamin D (25OHD) and vitamin D receptors polymorphisms (VDRs) are associated with cancer risk. The biological effects of vitamin D are mediated by an abundance of the vitamin D binding protein (DBP) and VDRs. The gene for the vitamin D–binding protein, known as ‘‘group-specific component’’ (Gc), is also a logical candidate in the vitamin D pathway because its major function is to transport vitamin D metabolites in the blood to different target organs. Variants in this gene have been shown to alter plasma concentrations of 25OHD and several studies investigated Gc SNPs and DBP in association with cancer risk with controversial results. Thus we carried out a comprehensive literature search and meta-analysis to investigate these associations. A systematic literature search was performed following a pre-defined protocol and using validated search strategies up to April 2014. We included for 24 independent studies for a total of 38,331 cases and 25,050 controls, from several countries Australia, Canada and USA, Finland, Germany, the Netherlands, Spain, UK, China and Iran. Data collected concern the following cancer sites: skin (n. of estimates=1), bladder (n=2), breast (n=3), colon-rectum (n=5), endometrium (n=1), liver (n=1), esophagus (n=1), stomach (n=1), melanoma (n= 3), pancreas (n= 2), prostate (n= 5) and kidney (n=1). Through random effect models we calculated the Summary Odd Ratios (SORs) for serum DBP (n. of estimates=6) and the following polymorphisms: rs2282679 (n. of estimates=7), rs12512631 (n=4), rs7041 (n=17), rs4588 (n=12), rs1155563 (n=5) and rs1352844 (n=3). We found a significant 8% increase cancer risk at any site for rs4588 variant (dominant model) and a non significant decrease risk at increasing level of DBP: SOR= 0.94 (0.86-1.02) per an increase of 1000 nmol/L. We evaluated also departure from Hardy-Weinberg equilibrium (HWE) in controls and sensitivity analyses excluding studies that do not respect HWE did not show important changes in results. No indication of publication bias was found. In conclusion we found some interesting associations indicating a possible role of DBP in cancer etiology. Further studies should consider also the role of the ‘free’ unbound part of 25OHD, that drives many of the non-classical actions of vitamin D, and it is dependent on the concentration of DBP.