Scleroderma Twin Study

描述（由申请人提供）：系统性硬化症（SSc; Scleroderma）是一种病因不明的结缔组织疾病，与显著的发病率和死亡率相关。长期以来，人们一直认为SSc可能是由环境因素引起的，尽管这些环境因素尚未被确定。评估环境和遗传对疾病发展的影响的黄金标准是对双胞胎的研究。几年前，我们对患有SSc的双胞胎进行了一项横断研究，结果显示，同卵双胞胎（MZ）和异卵双胞胎（DZ）的疾病一致性约为5%。已发表的关于家族性SSc病例的研究，以及我们的双胞胎研究结果表明，SSc可能发生在遗传易感背景的个体中，暴露于适当的环境触发因素或通过获得性遗传变化。因此，我们在特定的目标1中提出，使用双胞胎队列和大型SSc患者队列以及匹配的对照来确定可能与SSc相关的环境因素。由于表观遗传调控已成为介导基因表达和疾病表型表现的重要机制，因此我们设计了特异性目的2来比较参与我们研究的双胞胎的DNA甲基化谱。最后，我们将探讨效果

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc; Scleroderma) is a connective tissue disease of unknown etiology that is associated with significant morbidity and mortality. It has long been presumed that SSc likely results from environmental triggers, although these environmental insults have not been identified. The gold standard for assessing the role of environmental and inherited genetic effects on the development of a disease is the study of twins. A cross sectional study of twins with SSc we conducted several years ago showed a comparable concordance for disease of approximately 5% in monozygotic (MZ) and dizygotic (DZ) twins. Published research on familial cases of SSc, in conjunction with findings from our twin study, suggests that SSc likely develops in individuals with a genetically susceptible background upon exposure to appropriate environmental triggers or via acquired genetic changes. We therefore propose in specific aim 1 to identify environmental factors that may associate with SSc using the twin cohort and a large cohort of SSc patients and matched controls. Since epigenetic regulation has emerged as an important mechanism mediating gene expression and the manifestation of a disease phenotype, specific aim 2 is designed to compare the DNA methylation profile of twins participating in our study. Lastly, we will explore the effect of environmental factors on DNA methylation in specific aim 3. Our findings will significantly advance our understanding of disease pathogenesis in SSc, provide novel insights into epigenetic mechanisms underlying the disease, and identify a causal relationship between environmental factors and altered DNA methylation. Our findings will propel progress in the field and provide new avenues for research for mentees to facilitate their research and allow them to establish their own independent research programs. These mentees will be integral participants in the PI's program throughout the award period. The PI will mentor young physician scientists in the assessment of SSc in patients and the absence of disease in healthy twins, the evaluation of Raynaud phenomenon, obtaining informed consent, administration of questionnaire to patients and controls, use of clinical samples, the examination of DNA methylation profiles, the application of the University of Pittsburgh Scleroderma SerumBank and matching clinical Database to their research projects, and the analysis of environmental factors on DNA methylation. Together, these approaches will train the mentees in epidemiology, identification of risk factors, environmental medicine, and clinical epigenetics. The mentoring goals of this application also include mentoring young physician scientists in patient-oriented research, grantsmanship, manuscript writing, responsible conduct of research, and career development. The PI's reputation as an excellent mentor coupled with the collaborative and supportive environment at the University of Pittsburgh, the resources available at the institution and via the CTSI, and the resources of the Scleroderma Center of Pittsburgh, provide the perfect environment for attracting and training successful physician scientists. Our success will provide a pipeline of clinical investigators to continue the mission of treating patients and identifying te cause and cure for Scleroderma and related diseases.