Lymphocyte CpG methylation changes and brain pathology in Restless Legs Syndrome

不宁腿综合征中淋巴细胞 CpG 甲基化的变化和脑病理学

基本信息

批准号：
9443755
负责人：
CHRISTOPHER J EARLEY
金额：
$ 60.24万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9443755
关键词：
Adult Affect Alpha Cell American Autopsy Biological Biological Markers Biology Brain Brain Pathology Central Nervous System Diseases Child Childhood Chromosome Mapping Chronic Kidney Failure Consequentialism DNA Development Disease Dominant Genes Elderly Elements Environmental Exposure Environmental Risk Factor Epigenetic Process Evaluation Exposure to Family Study Family history of Fetal Development Freezing Frequencies Future General Population Genetic Genetic Risk Genetic Screening Genotype Heritability Homeostasis Inheritance Patterns Intervention Iron Iron deficiency anemia Lead Life Link Long-Term Effects Lymphocyte Magnetic Resonance Imaging Measures Medical Methylation Modeling Mothers Mutation Nature Pathology Patients Peripheral Phase Phenotype Population Populations at Risk Predisposition Pregnancy Prevalence Prevention Preventive Process Public Health Quality of life Reproducibility Research Resistance Resolution Restless Legs Syndrome Risk Sampling Sensory Severities Severity of illness Substantia nigra structure Symptoms System Techniques Time Tissues Validation age related disorder risk early life exposure endophenotype epidemiology study epigenetic marker genome wide association study high risk infancy insight interest iron deficiency motor disorder nervous system disorder prenatal exposure prevent pyrosequencing response treatment response

项目摘要

Restless leg syndrome (RLS) is a common sensory-motor disorder that has a significant negative impact on the quality of life for estimated 8 million Americans1. Low brain iron, despite the absence of currently existing systemic iron deficiency, appears to be an important part of the pathology and an important endophenotype of the disease identifiable with special MRI techniques. One hypothesis is that an initial, early exposure to iron deficiency (ID) leads to a cell protective response, which, despite the "normalization" of peripheral iron status, can have a long-term effect on cellular iron homeostasis that sensitive the system to later challenges2. Epigenetic processes provide a mechanism by which environmental factor can influence later life genetic. Thus early exposure to ID condition may lead to epigenetic changes that set up the risk of developing RLS with later exposure to environmental factors (e.g., pregnancy, iron deficiency, chronic renal failure, age-related factors) leading to the phenotypic expression of the underlying genotype 2. RLS also shows a dominant inheritance pattern with children from affected mothers having a higher risk than from affected fathers7, yet no dominant or co-dominant gene(s) has been found in GWAS and family studies. In utero exposure to ID with consequential epigenetic changes may help explain this heritability nature in RLS. Our primary interest is to identify RLS-relevant epigenetic factors in readily accessible tissues, so later studies can use them as biomarkers of disease risk and possible indicators of RLS biology and associated medical conditions. CpG methylation changes in lymphocytes, which have previously been shown to have cellular changes similar to that seen in RLS autopsy brains2, will be used. MRI will be used to measure iron concentrations in the substantia nigra (SN), which is a well-accepted brain-related endophenotype of the disease. ID is the most significant and well-recognized environmental factor associated with triggering RLS symptoms in adults58. The prevalence of RLS in the most extreme ID conditions (iron deficiency anemia (IDA)) is 30-40% compared to 5% prevalence of RLS in the general population3,59,60. A severe iron deficient condition will be used to delineate two groups with a high degree of discriminative ability to identify disease-relevant or disease-irrelevant epigenetic biomarkers. Epigenetic changes, unlike genetic change, are preventable and in some cases reversible. Preventing ID, therefore, could potentially have the significant impact on RLS development. If a genetic-epigenetic interaction is identified, then screening for the genetic risk component and applying preventive steps in this group could dramatic change the public health risk of RLS. A similar option may be indicated for those with a family history of RLS. The findings would clearly impact the future direction of research in RLS with more of emphasis on public health risk and prevention of iron deficiency.

不宁腿综合症（RLS）是一种常见的感觉运动障碍，对身体产生显着的负面影响。估计 800 万美国人的生活质量1。脑铁含量低，尽管目前尚不存在系统性缺铁似乎是病理学的重要组成部分，也是重要的内表型可通过特殊 MRI 技术识别的疾病。一种假设是，最初、早期接触铁缺乏（ID）会导致细胞保护反应，尽管外周铁状态“正常化”，可以对细胞铁稳态产生长期影响，使系统对以后的挑战敏感2。表观遗传过程提供了一种环境因素可以影响晚年遗传的机制。于是早暴露于 ID 条件下可能会导致表观遗传变化，从而增加以后出现不宁腿综合征的风险暴露于环境因素（例如怀孕、缺铁、慢性肾功能衰竭、年龄相关因素）导致潜在基因型 2 的表型表达。RLS 也显示出显性遗传受影响母亲的孩子比受影响父亲的孩子有更高的风险7，但没有显性或 GWAS 和家族研究中已发现共显性基因。在子宫内暴露于 ID 并产生后果表观遗传变化可能有助于解释不宁腿综合征的遗传性。我们的主要兴趣是在容易接近的组织中识别与 RLS 相关的表观遗传因素，因此后续研究可以将它们用作疾病风险的生物标志物以及 RLS 生物学和相关医学的可能指标状况。淋巴细胞中 CpG 甲基化的变化，此前已被证明与细胞将使用类似于 RLS 尸检大脑中所见的变化。 MRI将用于测量铁黑质（SN）中的浓度，这是一种被广泛接受的与大脑相关的内表型疾病。 ID 是与触发 RLS 相关的最重要且公认的环境因素成人的症状58。最极端的 ID 状况（缺铁性贫血 (IDA)）中 RLS 的患病率普通人群中 RLS 的患病率为 30-40%，而 RLS 的患病率为 5%3,59,60。严重缺铁的情况将用于划分两个具有高度辨别能力的群体，以识别疾病相关或与疾病无关的表观遗传生物标志物。与遗传变化不同，表观遗传变化是可以预防的，并且在某些情况下是可逆的。防止身份识别，因此，可能会对 RLS 的发展产生重大影响。如果遗传-表观遗传相互作用确定后，就可以筛查遗传风险成分并在该组中采取预防措施 RLS 的公共卫生风险发生巨大变化。对于有家族史的人可能会提出类似的选择的 RLS。这些发现显然会影响 RLS 的未来研究方向，并且更加强调公共卫生风险和缺铁的预防。