Methylomic biomarkers for magnesium deficiency and colon neoplasia prevention

镁缺乏和结肠肿瘤预防的甲基组生物标志物

基本信息

批准号：
9210072
负责人：
QI DAI
金额：
$ 63.66万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9210072
关键词：
Adverse effects Affect Biological Biological Markers Calcium Cardiovascular Diseases Clinic Clinical Trials Colonic Neoplasms Colorectal Colorectal Cancer Colorectal Neoplasms Cytosine DNA DNA Methylation Diet Disease Environmental Exposure Gene Expression Gene Targeting General Population Genes Genome Gold Health Homeostasis Human Individual Insulin Insulin Resistance Intake Leukocytes Link Magnesium Magnesium Deficiency Malignant Neoplasms Metabolic Metabolic syndrome Methylation Modification Non-Insulin-Dependent Diabetes Mellitus Nutrient Participant Pathway interactions Patients Phase Pilot Projects Placebos Play Population Prevention Price Protocols documentation Research Research Personnel Risk Role Sensitivity and Specificity Serum Techniques Testing Tetanus Helper Peptide Tissues Update bisulfite sequencing calcium intake clinical Diagnosis clinical practice colon carcinogenesis colorectal cancer prevention disorder risk epidemiology study epigenome-wide association studies epigenomics high risk indexing individualized prevention mortality novel oxidation public health relevance rectal specific biomarkers

项目摘要

DESCRIPTION (provided by applicant): Five US studies using the Mg tolerance test, the "gold standard" test of Mg status, indicated that >50% participants had Mg deficiency. In our ongoing US trial, we have found a similar result. In growing recognition of the importance of Mg in human health, very recently, Mg was selected by the US Federal Dietary Reference Intake (DRI) Committee to update the DRI. In US and other populations at high risk of Mg deficiency, high Mg intake has been linked to reduced risk of colorectal neoplasia, insulin resistance, metabolic syndrome, type 2 diabetes, and cardiovascular disease (CVD). Conversely, in populations not at high risk of Mg deficiency, high Mg intake has been related to increased risk of total mortality (e.g. total cancer, colorectal cancer, and CVD), particularly when calcium intak is low. These observations suggest that the associations between high Mg intake and disease risks may completely differ by the underlying Mg status. Due to major limitations, the Mg tolerance test is not used in conventional clinical practice and rarely used in research. Instead, serum Mg is used for clinical diagnosis. However, serum Mg performs very poorly at identifying those with Mg deficiency. There is a great need to develop implementable, sensitive, and specific biomarkers which can be easily used for identifying people with Mg deficiency. Without such a marker, it is impossible to develop effective strategies that minimize adverse effects by targeting those who, as a result of Mg deficiency, are at risk of common diseases. It is known that DNA methylation changes are inducible by environmental exposures, including nutrients, and reversible when the exposure disappears. There are two major types of cytosine modifications in DNA, 5-hydroxymethylcytosine (5-hmC) and 5-methylcytosine (5-mC). 5-mC is often associated with suppressed gene expression. 5-hmC, generated by the oxidation of 5-mC, is specifically enriched in expressed genes and plays a critical role in activating and/or maintaining gene expression. However, current epigenomic profiling platforms cannot distinguish 5-hmC from 5-mC. Just recently, our collaborator, Dr. Chuan He (HHMI Investigator), established a novel and state of the art technique, TAB-Seq & TAB-Array protocol, which can separate 5-hmC from 5-mC in the genome. Our pilot studies indicate that Mg intake or treatment significantly affects methylation capacity, 5-mC and 5-hmC biomarkers. Our findings suggest blood leukocyte 5-hmC/5-mC biomarkers may serve as more sensitive biomarkers to identify Mg deficiency than serum Mg. Thus, a comprehensive epigenome-wide association study (EWAS) may help to identify the most sensitive 5-hmC/ 5- mC biomarkers for Mg deficiency. We propose to identify 5-hmC/5-mC biomarkers for Mg deficiency by a 4- phase EWAS study in the "Personalized Prevention of Colorectal Cancer Trial [PPCCT, R01CA149633; PI, Dai & Yu]" with a total of 240 participants. Mg tolerance test will be used as the gold standard. Finally, using newly identified biomarkers, we will evaluate if 12-week Mg treatment reduces TRPM7 expression, essential in Mg homeostasis and colorectal carcinogenesis, in rectal tissues only among those with Mg deficiency.

描述（由申请人提供）：五项使用镁耐受性测试（镁状态的“黄金标准”测试）的美国研究表明，>50% 的参与者患有镁缺乏症。在我们正在进行的美国试验中，我们发现了类似的结果。人们越来越认识到镁对人类健康的重要性，最近，美国联邦膳食参考摄入量 (DRI) 委员会选择镁来更新 DRI。在美国和其他镁缺乏高风险人群中，高镁摄入量已成为人们关注的焦点。镁摄入量与结直肠肿瘤、胰岛素抵抗、代谢综合征、2 型糖尿病和心血管疾病 (CVD) 的风险降低有关，在镁缺乏风险不高的人群中，高镁摄入量与总死亡率风险增加有关。（例如总癌症、结直肠癌和心血管疾病），特别是当钙摄入量较低时，这些观察结果表明，由于镁耐受性的主要限制，高镁摄入量与疾病风险之间的关联可能完全取决于潜在的镁状态。常规临床实践中不使用血清镁检测，也很少用于研究，但血清镁在识别镁缺乏症方面表现非常差，因此非常需要开发可实施的、灵敏的和可检测的方法。可以轻松用于识别镁缺乏症患者的特定生物标记物，如果没有这样的标记物，就不可能针对那些因镁缺乏症而面临常见疾病风险的人制定有效的策略，以最大程度地减少不良影响。已知DNA甲基化变化是DNA 中存在两种主要类型的胞嘧啶修饰，即 5-羟甲基胞嘧啶 (5-hmC) 和 5-甲基胞嘧啶 (5-mC)，通常与环境暴露（包括营养物质）诱导，并且在暴露消失后可逆。 5-hmC 由 5-mC 氧化产生，在表达基因中特异性富集，并在激活和/或激活中发挥关键作用。然而，当前的表观基因组分析平台无法区分 5-hmC 和 5-mC。就在最近，我们的合作者 Chuan He 博士（HHMI 研究员）建立了一种新颖且最先进的技术：TAB-Seq & TAB。 -阵列方案，可以将基因组中的 5-hmC 与 5-mC 分开。我们的初步研究表明，镁的摄入或治疗显着影响甲基化能力、5-mC 和 5-hmC 生物标志物。研究结果表明，血液白细胞 5-hmC/5-mC 生物标志物可能是比血清镁更敏感的生物标志物，可用于识别镁缺乏症，因此，全面的表观基因组范围关联研究 (EWAS) 可能有助于识别最敏感的 5-hmC/5。 - 镁缺乏症的 mC 生物标志物我们建议通过“结直肠癌的个性化预防”中的 4 阶段 EWAS 研究来确定镁缺乏症的 5-hmC/5-mC 生物标志物。试验[PPCCT，R01CA149633；PI，Dai & Yu]”，共有 240 名参与者。镁耐受测试将用作黄金标准。最后，使用新鉴定的生物标志物，我们将评估 12 周的镁治疗是否会降低 TRPM7 表达。，对于镁稳态和结直肠癌发生至关重要，仅在镁缺乏的直肠组织中存在。