Gaining a more thorough understanding of the genetic underpinnings of RLS should eventually help us to better understand the underlying pathophysiology of RLS. This should therefore also help us to develop more sophisticated and personalized methods of treatment.

我们的研究小组已经参与了一项全基因组关联研究(GWAS). This method screens for natural, single-unit variances in the DNA structure (like looking for a small difference in a single pearl compared to all the other pearls that make up a necklace). 迄今为止，使用GWAS技术已经鉴定了几个基因. These genes have one or more small alterations in their DNA structure that are associated with increased risk of developing RLS. These small changes are not “causing” the disease in the same sense that mutations in clotting factor genes cause bleeding problems in a hemophilia. 这些基因上的微小差异, in turn, 微小的影响，如果在多个基因中叠加，可能会产生更大的风险. 这意味着我们需要了解这些不同基因之间的动态关系. 尽管这些基因现在看起来彼此之间几乎没有关系, they all relate to RLS. We are working on discovering what those dynamic relationships are by better understanding the biological roles that each of these genes play within cells. 如果我们能建立这些与rls相关的基因和它们的蛋白质产物之间的关系, 那么我们就可以开始了解RLS特有的特定生物机制. From that we can develop potential interventions that might be used to change that system in a positive and personalized way.

In a large family history study, we demonstrated that the risk of inheritance looked very much like it was related to a dominant gene. 但是，尽管付出了很多努力和多次研究，仍未发现一个单一的显性基因. The genes found using GWAS only provide about 7% of the overall genetic risk and do not account for the dominant nature of the inheritance of this disease. 我们在约翰·霍普金斯大学的研究小组已经着手研究一种新的基因分析方法, which involves looking, not just at the gene, but also at the multi-level factors that control how a gene is eventually transcribed into a protein. Certain environmental triggers can change how a gene is activated by activating complex biological processes referred to collectively as “epigenetic” mechanisms. These epigenetic mechanisms place (or remove) the equivalent of a small 'tag' on the gene(s) that may then alter the gene’s expression. 这些表观遗传变化可以代代相传. Thus an epigenetic approach may provide the elusive answer as to what is inherited across family members with RLS.

我们的环境条件可以不可逆转地改变基因的激活方式和类型, 这个过程被称为表观遗传学. It makes intuitive sense that an individual with a fixed set of genes should be able to modify expression of those genes based upon the individual’s environmental challenges. Unlike genetic changes, which are fixed, epigenetic changes usually occur under environmental stress and thus could be prevented or even reversed if we can identify the stressors or the genes that have been modified. The results from our large family study identify “environmental factors” as contributing more to the risk of developing RLS than that from just genes alone. 问题是环境因素是什么? We have identified iron insufficiency as the leading environmental factor contributing to the development of RLS. 儿童时期是否出现铁缺乏, pregnancy, 或者贯穿一个人的一生, 即使铁含量恢复正常，其后果也可能是永久性的. Our research has led to the discovery of altered brain iron regulation as a key component underlying RLS. We believe the alteration in brain iron regulation is a consequence of this environment-gene interaction. We are now striving to understand epigenetic and genetic factors regulated by environment stressors such as iron insufficiency and how they can permanently change brain iron regulatory mechanisms. 确定环境压力源的性质(持续时间)是很重要的, severity and timing) and the genes that are affected in order to potentially prevent or change the outcome, 是什么导致了睡眠睡动症的症状.

我们使用的动物和细胞模型代表了我们目前所知道的基因的各个方面, 与RLS相关的表观遗传和其他生物学机制. By utilizing these models, we can gain an understanding of how certain genes relate to other genes and the consequence of this dynamic gene interaction, 尤其是在大脑调节方面. We can explore the consequence of environmental stressors like iron deficiency at different ages of the animals and then look for epigenetic changes within the RLS-related genes or in genes not yet identified. In the models, 我们可以提出问题, collect data, and grow a tangible, viable, and operationally significant dynamic system of the underlying biology and potential pathophysiology behind RLS. 我们的模型第一次提供了一个机会，来实际测试治疗这种疾病的新化合物.