Vitamin D Status, Genetic Variation in Vitamin D Signaling and Metabolism, and Ri

描述（由申请人提供）：流行病学调查表明，维生素D代谢物25(OH)D（激素125 (OH)2D的前体分子）的低血清水平与结直肠肿瘤的风险相关，尽管结果模棱两可，并且对这些生物标志物的性别或结直肠亚位点特异性关系知之甚少。从功能的角度来看，125 (OH)2D在结直肠癌细胞系中具有抗增殖、促分化和生长抑制作用。因此，有令人信服的证据表明，活性维生素D代谢物在降低结直肠癌的风险中发挥作用，但在细胞水平上达到最佳水平的125 (OH)2D的最佳方法尚不清楚，维生素D受体（VDR）或负责代谢125 (OH)2D的初级酶的遗传变异在组织水平上的功能影响尚不清楚。初步证据表明，VDR中的snp可能影响循环中125 (OH)2D的浓度；此外，CYP27B1和CYP24A1两种酶在该分子的代谢稳态中尤为重要。虽然已经对VDR的功能和流行病学关联进行了研究，但很少有关于这两种关键酶遗传变异的分子或流行病学影响的研究。此外，维生素D可能发挥其化学预防作用的机制尚不清楚，尽管我们的团队以及其他人的研究表明，APC、b-连环蛋白和125 (OH)2D-VDR代表了结肠细胞增殖细胞内调节因子的分子“十字路口”。本研究的具体目的是：1)测量结肠直肠腺瘤复发临床试验参与者血液中25(OH)D和125 (OH)2D的浓度，并评估这些变量与腺瘤复发几率之间的关系；2)研究参与者VDR、CYP27B1和CYP24A1基因型变异，评估snp与结直肠腺瘤复发几率和循环维生素D代谢物浓度之间的关系；3)阐明CYP27B1和CYP24A1基因选择多态性在人Caco-2结肠细胞中的功能作用；4)研究VDR（和VDR多态性变异）与2-catenin之间的分子串扰，以及APC对这些信号转导通路的功能影响。次要目的包括调查维生素D代谢物与腺瘤和晚期腺瘤复发之间的性别分层关联，以及评估这些关联是否因结直肠亚部位而异。这项工作有可能通过改善维生素D状态为结直肠癌的发生提供一种具有成本效益的预防措施，并为维生素D代谢关键酶的遗传变异的功能影响以及可能调节维生素D代谢物和VDR的信号通路（包括APC和b-catenin）的阐明提供新的分子证据。

DESCRIPTION (provided by applicant): Epidemiological investigations have demonstrated that low serum levels of the vitamin D metabolite 25(OH)D, the precursor molecule for the hormone 1,25(OH)2D, are associated with risk of colorectal neoplasia, though results have been equivocal, and little is known about sex- or colorectal sub-site-specific relationships for these biomarkers. From a functional standpoint, anti-proliferative, pro-differentiating, and growth inhibitory effects of 1,25(OH)2D have been shown in colorectal cancer cell lines. Thus, there is compelling evidence that active vitamin D metabolites play a role in reducing the risk for colorectal neoplasia, but the best approach for attaining optimal levels of 1,25(OH)2D at the cellular level are not known, and the functional effects of genetic variation in the vitamin D receptor (VDR) or in primary enzymes responsible for metabolism of 1,25(OH)2Dat the tissue level are poorly understood. Preliminary evidence indicates that SNPs in VDR may influence circulating concentrations of 1,25(OH)2D;further, two enzymes, CYP27B1 and CYP24A1, are of particular importance in metabolic homeostasis of this molecule. Although there has been research into the functionality of and epidemiological associations of the VDR, there are few studies of the molecular or epidemiological effects of genetic variation in these two key enzymes. Further, the mechanisms through which vitamin D may exert its chemopreventive effects are unknown, though work by our group as well as others suggests that APC, b-catenin, and 1,25(OH)2D-VDR represent a molecular "crossroads" of intracellular regulators of colonic cell proliferation. The specific aims of the proposed work are to 1) Measure circulating 25(OH)D and 1,25(OH)2D concentrations among participants in clinical trials of colorectal adenoma recurrence, and assess the association between these variables and the odds of adenoma recurrence; 2) Genotype study participants for variation in VDR, CYP27B1 and CYP24A1 and evaluate the association between SNPs and odds for colorectal adenoma recurrence and circulating concentrations of vitamin D metabolites; 3) Elucidate the functional effects of selected polymorphisms in the CYP27B1 and CYP24A1 genes in human Caco-2 colonic cells; 4) Investigate molecular crosstalk between VDR (and VDR polymorphic variants) and 2-catenin, as well as the functional influence of APC on these signal transduction pathways. Secondary aims include investigation of sex-stratified associations between vitamin D metabolites and recurrence of adenomas and advanced adenomas, as well as assessment of whether these associations vary by colorectal sub-site. This work has the potential to offer a cost-effective preventative measure for colorectal carcinogenesis through improving vitamin D status, as well as to illuminate novel molecular evidence for the functional effects of genetic variation in key enzymes of vitamin D metabolism, and for the elucidation of signaling pathways, including APC and b-catenin, that likely modulate the actions of vitamin D metabolites and VDR. PUBLIC HEALTH RELEVANCE: The proposed work has the potential to offer a cost-effective preventative measure for colorectal carcinogenesis through improving vitamin D status, as well as providing molecular evidence for the functional effects of genetic variation in key enzymes in the vitamin D pathway, and for the pathways through which vitamin D metabolites are acting, including via APC/B-catenin.