Genetic Variants Influencing Response to Vitamin D in Colorectal Chemoprevention

描述（由申请人提供）：越来越多的证据支持维生素D在结直肠中具有抗肿瘤作用的假设，维生素D补充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照射不足，通常需要补充维生素D来提高维生素D水平。然而，目前尚不清楚遗传因素如何影响对维生素D补充的反应。有趣的是，最近的两项全基因组关联研究（GWAS）发现，循环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，它受到四个位点变异的影响，这些位点位于与维生素D运输和代谢相关的关键蛋白质编码基因中或附近：1)维生素D结合蛋白（DBP）， 2) 7-脱氢胆固醇还原酶（DHCR7）， 3) 25-羟化酶CYP2R1, 4) 24-羟化酶CYP24A1。目前尚不清楚这些影响25(OH)D水平的“GWAS撞击”是否也会影响维生素D补充后25(OH)D的增加，并最终影响结直肠肿瘤的风险。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开始解决这个问题，随后在未来的研究中研究基因对结直肠肿瘤风险的影响。这项工作将以一种高效且具有成本效益的方式进行，利用来自大约2188名参与者的数据和生物标本，这些参与者正在进行一项nci资助的随机临床试验，维生素D3 （1000 IU/天）和钙（1200 mg/天）补充剂用于预防结直肠腺瘤：维生素D/钙息肉预防研究。来自这些参与者的DNA将用于GWAS分析中与25(OH)D水平相关的四个位点中每个位点的最具统计学意义的snp基因型。将使用线性回归来估计这些snp在补充一年后对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，是否与这些基因变异相互作用，以改变对维生素D补充的反应。这项研究可能会确定那些对维生素D补充反应不良的个体，并且可能对了解不同基因型的个体是否需要不同剂量的维生素D具有临床意义。由于维生素D不足的普遍存在以及结直肠癌、骨质疏松症和其他与维生素D缺乏相关的常见疾病的高发，这项工作的公共卫生意义是实质性的。

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. PUBLIC HEALTH RELEVANCE: This research will investigate the effect of specific polymorphisms in key genes involved in vitamin D metabolism and transport on the increase in vitamin D levels that are achieved in response to vitamin D supplementation for the prevention of colorectal adenomas, precursors to cancer. The public health significance of this work is substantial due of the prevalence of vitamin D insufficiency and the high incidence of colorectal cancer and other diseases associated with poor vitamin D status.