Filaggrin Mutations and the Prognosis of Atopic Dermatitis

聚丝蛋白突变与特应性皮炎的预后

• 批准号: 7808038
• 负责人: David Margolis
• 金额: $ 54.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-18 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808038
• 关键词: 1q21; 1q21.3; Adult; Affect; African American; Age; Allergic rhinitis; Antibodies; Asthma; Atopic Dermatitis; Child; Childhood; Chromosomes; Chronic; Cohort Studies; Complex; Country; Cytoplasmic Granules; Defect; Diagnosis; Disease; Disease remission; Eczema; Enrollment; Environmental Risk Factor; European; European Union; Evaluation; Exanthema; Filament; Functional disorder; Genes; Genetic; Goals; Hypersensitivity; Ichthyosis Vulgaris; IgE; Immunologics; Individual; Inflammatory; International; Investigation; Laboratories; Mutation; Natural History; Odds Ratio; Pathogenesis; Patients; Pharmaceutical Preparations; Physicians; Population; Population Heterogeneity; Prevalence; Production; Proteins; Pruritus; Publishing; Recurrence; Registries; Relapse; Research Personnel; Seminal; Severities; Severity of illness; Skin; Stratum Granulosum; Symptoms; Triad Acrylic Resin; Variant; Work; atopy; base; biobank; caucasian American; clinical phenotype; cohort; cost; filaggrin; infancy; keratinocyte; keratohyalin; loss of function; loss of function mutation; outcome forecast; post-market; prospective; protein aggregate; skin disorder; stratum corneum basic protein precursor; working group

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) is a highly pruritic chronic inflammatory skin disease that predominantly presents during infancy but may also present during childhood or adulthood. AD is a common skin disease characterized by recurrent episodes of itching and a chronic, relapsing course. The lifetime prevalence of AD is about 5-20 percent. Many with AD will also suffer with asthma and allergic rhinitis. The simple act of reliably identifying affected patients with AD and prognosticating on the natural history of their illness has been difficult. Clues on the severity of atopic dermatitis should center on a better understanding of the pathogenesis of this disorder. Many have assumed that the pathogenesis is based on genetic and environmental factors and that these factors influenced the clinical phenotype of the disorder. Most investigations on the pathogenesis of AD have centered on immunologic mechanisms and evaluations. However, starting in 2006 several seminal studies were published that may potentially revolutionize our understanding of the pathophysiology of AD. These studies described a defect in the skin barrier that is strongly associated with AD. This defect was due to a loss- of-function mutation for the production of a protein called filaggrin (FLG). The gene is located on chromosome 1q21. This gene encodes for profilaggrin, which is the principal constituent of the keratohyalin granule found in keratinocytes and the precursor for filaggrin. Based on studies using the first two sequenced FLG loss-of- function variants, the odds ratio of association among those with AD as compared to those without AD was between 8 and 14. However, the type of FLG loss-of-function mutations varies by cohort studied with the majority of those currently studied being of European ancestry. No large studies have been conducted on the heterogenous US population and very few have evaluated the prognosis of those who have AD and a FLG loss-of-function mutation. The Pediatric Eczema Elective Registry (PEER) is an ongoing prospective 10-year observational registry that is part of a post-marketing commitment by Novartis to the FDA and the European Drug Agency. The nearly 4,000 US children currently enrolled in the registry represent a unique opportunity to evaluate the natural history of AD in a group of children with a physician-confirmed diagnosis of AD. To that end we plan to establish a US national biobank of individuals with physician confirmed atopic dermatitis; to fully explore, sequence and identified FLG loss-of-function mutations (gene 1q21.3) unique to our ethnically diverse cohort; and to determine the association of the FLG loss-of-function mutations with respect to the natural history of AD in the PEER cohort. Atopic dermatitis is a chronic itchy rash of childhood and is estimated to cost these country 1.6 billion dollars per year. Over a lifetime, between 5 and 20 percent of the population will suffer from this disorder. Very recent work has shown that many with this disorder will have a genetic defect that alters how their skin protects them from the outside world. The goal of this study is to see how this defect may affect the diverse US population and whether the prognosis is different for those with this defect as compared to those who do not have this defect.

描述（由申请人提供）：特应性皮炎（AD）是一种高度过敏性慢性炎症性皮肤病，主要出现在婴儿期，但也可能出现在儿童期或成年期。AD是一种常见的皮肤病，其特征在于反复发作的瘙痒和慢性复发性病程。AD的终生患病率约为5- 20%。许多AD患者还患有哮喘和过敏性鼻炎。可靠地识别受影响的AD患者并对其疾病的自然史进行解释的简单行为一直很困难。特应性皮炎的严重性的线索应该集中在更好地了解这种疾病的发病机制。许多人认为发病机制是基于遗传和环境因素，这些因素影响了疾病的临床表型。目前对AD发病机制的研究主要集中在免疫学机制和评价方面。然而，从2006年开始，发表了几项开创性的研究，可能会彻底改变我们对AD病理生理学的理解。这些研究描述了与AD密切相关的皮肤屏障缺陷。这种缺陷是由于一种叫做聚丝蛋白（FLG）的蛋白质产生的功能缺失突变造成的。该基因位于染色体1 q21上。该基因编码聚丝蛋白原，聚丝蛋白原是角质形成细胞中透明角质颗粒的主要成分，也是聚丝蛋白的前体。基于使用前两个测序的FLG功能丧失变体的研究，与没有AD的人相比，AD患者之间的关联的比值比在8和14之间。然而，FLG功能丧失突变的类型因研究的队列而异，目前研究的大多数是欧洲血统。尚未对异质性美国人群进行大规模研究，很少有研究评估AD和FLG功能丧失突变患者的预后。儿科湿疹择期登记研究（PEER）是一项正在进行的前瞻性10年观察性登记研究，是诺华公司向FDA和欧洲药品管理局作出的上市后承诺的一部分。目前登记的近4，000名美国儿童代表了一个独特的机会，可以在一组经医生确诊的AD诊断儿童中评估AD的自然史。为此，我们计划建立一个美国国家生物银行的个人与医生确认的特应性皮炎;充分探索，测序和识别FLG功能丧失突变（基因1q21.3）独特的种族多元化的队列;并确定相关的FLG功能丧失突变与AD的自然历史在同行队列。特应性皮炎是一种儿童期的慢性瘙痒性皮疹，据估计，这些国家每年花费16亿美元。在一生中，5%到20%的人口将患有这种疾病。最近的研究表明，许多患有这种疾病的人会有一种遗传缺陷，这种缺陷会改变他们的皮肤保护他们免受外界伤害的方式。这项研究的目的是了解这种缺陷如何影响不同的美国人群，以及与没有这种缺陷的人相比，这种缺陷的预后是否不同。