Lymphocyte CpG methylation changes and brain pathology in Restless Legs Syndrome

不宁腿综合征(RLS)是一种常见的感觉-运动障碍，对 估计有800万美国人的生活质量1。低脑铁，尽管目前缺乏现有的 全身性缺铁，似乎是该病病理的重要组成部分和重要的内表型。 这种疾病可以用特殊的磁共振成像技术来识别。一种假设是，最初的、早期的铁暴露 缺乏(ID)会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，从而使系统对以后的挑战敏感2。表观遗传 过程提供了一种机制，通过这种机制，环境因素可以影响后来的生命遗传。所以这么早 暴露在ID条件下可能会导致表观遗传变化，从而增加以后患RLS的风险 暴露于环境因素(如怀孕、缺铁、慢性肾功能衰竭、与年龄有关的因素) 导致潜在基因2的表型表达。RLS也表现出显性遗传 受影响母亲的孩子比受影响父亲的孩子风险更高的模式7，但没有显性或 共显性基因(S)已在家系和家系研究中发现。宫内暴露于ID会导致 表观遗传学改变可能有助于解释RLS的这种遗传性本质。 我们的主要兴趣是在容易获得的组织中识别与RLS相关的表观遗传因素，因此以后的研究 可以将它们用作疾病风险的生物标记物以及RLS生物学和相关医学的可能指标 条件。淋巴细胞中CpG甲基化的变化，以前已经被证明是细胞 将使用与RLS尸检大脑2中看到的类似的变化。核磁共振将被用来测量铁 黑质(SN)的浓度，这是一种被广泛接受的脑相关内表型 疾病。ID是与触发RLS相关的最重要和公认的环境因素 成年人的症状58。在最极端的缺铁性贫血(缺铁性贫血)条件下RLS的患病率 30%-40%，而普通人群中RLS的患病率为5%，359，60。严重的缺铁状况 将被用来描述两个具有高度区分能力的群体，以识别与疾病相关的或 疾病无关的表观遗传生物标记物。 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。阻止ID， 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 然后对遗传风险成分进行筛查并在这一组中采取预防措施 RLS的公共健康风险发生了戏剧性的变化。有家族史的人也可以选择类似的方案。 RLS的。这些发现将明显影响RLS未来的研究方向，更多地强调 公共健康风险与铁缺乏的预防。

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.