Filaggrin Mutations and the Prognosis of Atopic Dermatitis

描述（由申请人提供）：特应性皮炎（AD）是一种高度瘙痒的慢性炎症性皮肤病，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，其特征是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 患者还会患有哮喘和过敏性鼻炎。可靠地识别受影响的 AD 患者并预测其疾病的自然史的简单行为一直很困难。关于特应性皮炎严重程度的线索应集中于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，并且这些因素影响该疾病的临床表型。大多数关于 AD 发病机制的研究都集中在免疫机制和评估上。然而，从 2006 年开始，发表了几项开创性的研究，这些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名为丝聚合蛋白（FLG）的蛋白质产生功能丧失突变造成的。该基因位于染色体 1q21 上。该基因编码丝聚合蛋白原，它是角质形成细胞中发现的角质透明蛋白颗粒的主要成分，也是丝聚合蛋白的前体。根据使用前两个测序的 FLG 功能丧失变异的研究，AD 患者与非 AD 患者之间的关联比值比在 8 至 14 之间。然而，FLG 功能丧失突变的类型因研究队列而异，目前研究的大多数人具有欧洲血统。尚未对美国异质人群进行大型研究，也很少评估患有 AD 和 FLG 功能丧失突变的患者的预后。儿科湿疹选择性登记 (PEER) 是一项持续进行的 10 年前瞻性观察登记，是诺华向 FDA 和欧洲药品管理局做出的上市后承诺的一部分。目前登记的近 4,000 名美国儿童为评估一组经医生确诊患有 AD 的儿童的 AD 自然史提供了独特的机会。为此，我们计划建立一个美国国家生物库，其中包含经医生确认的特应性皮炎患者；充分探索、测序和识别我们不同种族群体特有的 FLG 功能丧失突变（基因 1q21.3）；并确定 FLG 功能丧失突变与 PEER 队列中 AD 自然史的关联。特应性皮炎是一种儿童期慢性瘙痒性皮疹，估计每年给这些国家造成 16 亿美元的损失。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都会有遗传缺陷，这种缺陷会改变他们的皮肤保护他们免受外界侵害的方式。本研究的目的是了解这种缺陷如何影响不同的美国人群，以及患有这种缺陷的人与没有这种缺陷的人相比，预后是否不同。

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.