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

• 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
• 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

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.

不宁腿综合征（RLS）是一种常见的感觉-运动障碍，对患者的生活质量有显著的负面影响。 估计800万美国人的生活质量1。脑铁含量低，尽管目前缺乏 全身性缺铁，似乎是一个重要的病理组成部分和一个重要的内在表型， 这种疾病可以用特殊的MRI技术来识别。有一种假设是，最初的早期接触铁 缺乏（ID）导致细胞保护性反应，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。后生 过程提供了一种机制，环境因素可以通过这种机制影响以后的生活遗传。这么早 暴露于ID条件下可能导致表观遗传变化，从而增加发生RLS的风险， 暴露于环境因素（例如，妊娠、缺铁、慢性肾衰竭、年龄相关因素） 导致潜在基因型2的表型表达。RLS也显示了显性遗传 受影响的母亲的孩子比受影响的父亲的孩子有更高的风险，但没有显性或显性遗传。 在GWAS和家系研究中发现了共显性基因。宫内暴露于ID， 表观遗传变化可能有助于解释RLS的遗传特性。 我们的主要兴趣是在容易获得的组织中识别RLS相关的表观遗传因子， 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。 条件淋巴细胞中的CpG甲基化变化，先前已显示其具有细胞毒性。 将使用与RLS尸检脑中所见相似的变化2。MRI将用于测量铁 黑质（SN）中的浓度，这是一种公认的脑相关的内源性表型， 疾病ID是与触发RLS相关的最重要和公认的环境因素 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 是30-40%，而一般人群中RLS的患病率为5% 3，59，60。严重缺铁的情况 将被用来描绘两个具有高度区分能力的组，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，在某些情况下是可逆的。防止身份证， 因此，可能会对RLS的发展产生重大影响。如果遗传和表观遗传的相互作用 确定，然后筛选遗传风险成分，并在该组中应用预防措施， 显著改变RLS的公共卫生风险。对于有家族史的人，可能会有类似的选择 的RLS。这些发现将明显影响RLS未来的研究方向，更多地强调 公众健康风险和预防铁缺乏症。