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

• 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
• 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

 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（由适用提供）：使用MG公差测试的五项研究，即MG状态的“黄金标准”测试，表明> 50％的参与者患有MG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。最近，最近，美国联邦饮食参考摄入委员会（DRI）委员会选择了MG在人类健康中的重要性，以更新DRI。在美国和其他高度缺乏风险的人群中，高MG摄入量与降低结直肠瘤，胰岛素抵抗，代谢综合征，2型糖尿病和心血管疾病（CVD）的风险有关。相反，在不存在MG缺乏症的高风险的人群中，高MG摄入量与总死亡率（例如总癌症，结直肠癌和CVD）的风险增加有关，尤其是当钙Intak钙较低时。这些观察结果表明，高MG摄入量与疾病风险之间的关联可能会因基础MG状态完全不同。由于主要局限性，在常规临床实践中不使用MG公差测试，并且很少在研究中使用。相反，血清MG用于临床诊断。但是，血清MG在识别Mg缺乏症的人方面的表现非常低。非常需要开发可实施，敏感和特定的生物标志物，可以轻松地用于识别MG缺乏症的人。没有这样的标记，就无法制定有效的策略，从而通过瞄准那些因毫克缺乏症而面临常见疾病的人来最大程度地减少不利影响。众所周知，通过环境暴露（包括营养素）可以诱导DNA甲基化变化，并且当暴露消失时可逆。 DNA，5-羟基甲苯蛋白（5-HMC）和5-甲基胞嘧啶（5-MC）中有两种主要类型的胞嘧啶修饰。 5-MC通常与抑制基因表达有关。 5-HMC是由5-MC氧化产生的，特异性地富含表达基因，并在激活和/或维持基因表达中起关键作用。但是，当前的表观分析平台无法将5-HMC与5-MC区分开。就在最近，我们的合作者Chuan He博士（HHMI研究者）建立了一种新颖的和状态，Tab-Seq＆Tab-Array协议，可以将5-HMC与基因组中的5-MC分开。我们的试点研究表明，MG摄入或治疗显着影响甲基化能力，5-MC和5-HMC生物标志物。我们的发现表明，血清细胞5-HMC/5-MC生物标志物可能比血清MG更敏感生物标志物鉴定MG缺乏症。这是一项全面的表观基因组协会研究（EWAS）可能有助于确定最敏感的5-HMC/5-MC生物标志物，以实现MG缺乏症。我们建议通过一项4期EWAS研究确定5-HMC/5-MC生物标志物在“个性化预防大肠癌试验[PPCCT，R01CA149633; PI，DAI＆YU]中”，共有240名参与者。 MG公差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Mg治疗是否会在直肠组织中仅在MG缺乏症的直肠组织中降低TRPM7的表达，这在MG稳态和有色癌变中必不可少。