Genetic Variants Influencing Response to Vitamin D in Colorectal Chemoprevention

影响结直肠化学预防中维生素 D 反应的遗传变异

基本信息

批准号：
8302297
负责人：
ELIZABETH L BARRY
金额：
$ 7.9万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302297
关键词：
25-hydroxyvitamin D 7-dehydrocholesterol reductase Address Age Antineoplastic Agents Binding Biological Markers Blood Body mass index Calcium Characteristics Chemoprevention Chemopreventive Agent Cholecalciferol Cholesterol Clinical Clinical Trials Code Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms Country DNA Data Diet Dietary intake Disease Dose Effectiveness Environmental Risk Factor Enzymes Epidemiologic Studies Funding Future Genes Genetic Genetic Polymorphism Genetic Variation Genotype Health Incidence Individual Linear Regressions Malignant Neoplasms Measurement Measures Metabolism Minority Mixed Function Oxygenases Osteoporosis Outcome Participant Pathway interactions Polyps Prevalence Prevention Proteins Public Health Randomized Clinical Trials Research Research Proposals Risk Single Nucleotide Polymorphism Smoking Status Source Staging Sun Exposure Supplementation Time Tissues Variant Vitamin D Vitamin D-Binding Protein Vitamins Work burden of illness colorectal cancer prevention cost effective genetic variant genome wide association study preclinical study response

项目摘要

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.

描述（由申请人提供）：大量且不断增长的证据支持这样的假设：维生素 D 在结直肠中具有抗肿瘤作用，补充维生素 D 是一种有前途的化学预防方法，可减轻这种疾病的负担。由于饮食摄入不足和阳光照射，通常需要补充维生素 D 来提高维生素 D 水平。然而，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 (GWAS) 发现循环 25-羟基维生素 D 水平 [25(OH)D]（最佳生物标志物）维生素 D 状态的变化受到四个位点变异的影响，这些位点位于编码与维生素 D 转运和代谢相关的关键蛋白的基因中或附近：1) 维生素 D 结合蛋白 (DBP)，2) 酶7-脱氢胆固醇还原酶(DHCR7)，3) 25-羟化酶CYP2R1，和4) 24-羟化酶CYP24A1。目前尚不清楚这些影响 25(OH)D 水平的“GWAS 命中”是否也会影响因补充维生素 D 而导致的 25(OH)D 增加，并最终影响结直肠肿瘤的风险。我们计划通过研究当前应用中补充剂反应的遗传影响来开始解决这个问题，随后在未来的研究中研究遗传对结直肠肿瘤风险的影响。这项工作将以高效且具有成本效益的方式进行，利用来自约 2,188 名参与者的数据和生物样本，这些参与者正在进行 NCI 资助的维生素 D3（1000 IU/天）和钙（1200 毫克/天）随机临床试验补充预防结直肠腺瘤：维生素 D/钙息肉预防研究。这些参与者的 DNA 将用于对 GWAS 分析中与 25(OH)D 水平相关的四个位点中每一个位点中最具统计学意义的 SNP 进行基因分型。线性回归将用于估计这些 SNP 对补充一年后 25(OH)D 水平增加的影响。此外，我们将探讨其他特征（例如体重指数和年龄）是否与这些遗传变异相互作用，从而改变对维生素 D 补充剂的反应。这项研究可能会识别出对维生素 D 补充剂反应不佳的个体，并且对于了解具有不同基因型特征的个体是否需要不同剂量的维生素 D 可能具有临床重要性。由于普遍存在，这项工作对公共卫生意义重大维生素 D 不足以及结直肠癌、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。