Genetic Variants Influencing Response to Vitamin D in Colorectal Chemoprevention

描述(由申请人提供)：大量不断增长的证据支持这样的假设，即维生素D在结直肠具有抗肿瘤作用，补充维生素D是一种有希望的化学预防方法，可以减轻这种疾病的负担。由于饮食摄入不足和阳光暴晒，经常需要补充剂来增加维生素D的水平。然而，目前尚不清楚遗传因素如何影响对补充维生素D的反应。有趣的是，最近的两项全基因组关联研究(GWA)发现，循环中的25-羟基维生素D水平[25(OH)D]是维生素D状态的最佳生物标志物，受到与维生素D运输和代谢相关的关键蛋白编码基因中或附近的四个基因位点变异的影响：1)维生素D结合蛋白(DBP)，2)7-脱氢胆固醇还原酶(DHCR7)，3)25-羟基酶CYP2R1，和4)24-羟基酶CYP24A1。目前尚不清楚这些影响25(OH)D水平的“GWA值”是否也影响了补充维生素D后25(OH)D水平的增加，并最终影响了大肠肿瘤的风险。我们计划在目前的应用中通过研究基因对补充剂反应的影响来解决这个问题，并随后在未来的研究中研究基因对结直肠肿瘤风险的影响。这项工作将通过使用来自NCI资助的正在进行的维生素D3(1000IU/天)和钙(1200毫克/天)补充剂预防结直肠腺瘤的随机临床试验：维生素D/钙息肉预防研究的大约2188名参与者的数据和生物显微镜，以高效和成本效益的方式进行。这些参与者的DNA将被用来在GWAS分析中与25(OH)D水平相关的四个基因座中的每一个上对最具统计学意义的SNPs进行基因分型。线性回归将被用来估计这些SNPs对补充一年后25(OH)D水平增加的影响。此外，我们将探索其他特征，如体重指数和年龄，是否与这些遗传变异相互作用，改变对维生素D补充的反应。这项研究可以确定对维生素D补充反应差的个体，并可能对了解具有不同基因型谱的个体是否需要不同剂量的维生素D具有临床重要性。由于维生素D缺乏的流行以及结直肠癌、骨质疏松症和其他与维生素D状况不佳相关的常见疾病的高发病率，这项工作的公共卫生意义重大。

DESCRIPTION (provided by applicant): A large and growing body of evidence supports the hypothesis that vitamin D has antineoplastic effects in the colorectum and that vitamin D supplementation is a promising chemopreventive approach to reduce the burden of this disease. Supplementation is often required to increase levels of vitamin D because of insufficient dietary intake and sunlight exposure. However, it is not known how genetic factors may influence the response to supplementation with vitamin D. Interestingly, two recent genome wide association studies (GWAS) found that the circulating 25-hydroxyvitamin D level [25(OH)D], the best biomarker of vitamin D status, is influenced by variants at four loci that are located in or near genes coding for key proteins associated with vitamin D transport and metabolism: 1) the vitamin D binding protein (DBP), 2) the enzyme 7-dehydrocholesterol reductase (DHCR7), 3) the 25-hydroxylase enzyme CYP2R1, and 4) the 24-hydroxylase enzyme CYP24A1. It is not known whether these "GWAS hits" that influence 25(OH)D level also influence the increase in 25(OH)D that is achieved in response to vitamin D supplementation and, ultimately, the risk of colorectal neoplasia. We plan to begin to address this issue by investigating genetic effects on the response to supplementation in the current application and, subsequently, to investigate genetic effects on risk of colorectal neoplasia in future research. This work will be performed in an efficient and cost effective manner by utilizing the data and biospecimens from approximately 2,188 participants in an on-going NCI-funded randomized clinical trial of vitamin D3 (1000 IU/day) and calcium (1200 mg/day) supplementation for the prevention of colorectal adenomas: the Vitamin D/Calcium Polyp Prevention Study. DNA from these participants will be used to genotype the most statistically significant SNPs at each of the four loci associated with 25(OH)D levels in the GWAS analyses. Linear regression will be used to estimate the effect of these SNPs on the increase in 25(OH)D levels following one year of supplementation. In addition, we will explore whether other characteristics, such as body mass index and age, interact with these genetic variants in modifying the response to vitamin D supplementation. This research may identify individuals who are at risk for poor response to vitamin D supplementation and may be of clinical importance to understanding if individuals with different genotypic profiles require different doses of vitamin D. The public health significance of this work is substantial due to the prevalence of vitamin D insufficiency and the high incidence of colorectal cancer, osteoporosis, and other common diseases associated with poor vitamin D status.