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: 8242639
• 负责人: David Margolis
• 金额: $ 29.75万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242639
• 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）是一种高度瘙痒性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或成年期。AD是一种常见的皮肤疾病，其特征是反复发作的瘙痒和慢性，复发的过程。阿尔茨海默病的终生患病率约为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历史这一简单的行为一直很困难。关于特应性皮炎严重程度的线索应该集中在更好地了解这种疾病的发病机制上。许多人认为发病机制是基于遗传和环境因素，这些因素影响疾病的临床表型。对阿尔茨海默病发病机制的研究大多集中在免疫机制和评价上。然而，从2006年开始，一些开创性的研究发表了，这些研究可能会彻底改变我们对阿尔茨海默病病理生理学的理解。这些研究描述了与阿尔茨海默病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。该基因位于染色体1q21上。该基因编码聚丝蛋白，它是角化细胞中发现的角透明素颗粒的主要成分，也是聚丝蛋白的前体。基于使用前两个FLG功能缺失变异序列的研究，AD患者与非AD患者的相关比值比在8 - 14之间。然而，FLG功能丧失突变的类型因研究队列而异，目前研究的大多数是欧洲血统。目前还没有针对美国异质人群的大型研究，很少有研究评估AD和FLG功能丧失突变患者的预后。儿科湿疹选择性注册（PEER）是一项正在进行的前瞻性10年观察性注册，是诺华公司对FDA和欧洲药品管理局上市后承诺的一部分。目前登记在册的近4000名美国儿童提供了一个独特的机会来评估一组经医生确诊为阿尔茨海默病的儿童的阿尔茨海默病的自然史。为此，我们计划建立一个美国国家生物银行，其中包括医生确诊的特应性皮炎患者；充分探索，测序和鉴定FLG功能丧失突变（基因1q21.3）独特的种族多样性队列；并确定FLG功能丧失突变与PEER队列中AD的自然史之间的关系。特应性皮炎是一种儿童期的慢性瘙痒性皮疹，据估计，该国每年为此花费16亿美元。在人的一生中，有5%到20%的人会患有这种疾病。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，以及与那些没有这种缺陷的人相比，有这种缺陷的人的预后是否不同。

项目成果

No Association of filaggrin copy number variation and atopic dermatitis risk in White and Black Americans.

美国白人和黑人中丝聚蛋白拷贝数变异与特应性皮炎风险之间没有关联。

• DOI: 10.1111/exd.14449
• 发表时间: 2022
• 期刊: Experimental dermatology
• 影响因子: 3.6
• 作者: Fulton,RachelL;Margolis,DavidJ;Sockler,PatrickG;Mitra,Nandita;Wong,XuanFeiColinCornelius;Common,JohnE
• 通讯作者: Common,JohnE

IGFBP7 as a potential therapeutic target in Psoriasis.

IGFBP7 作为银屑病的潜在治疗靶点。

• DOI: 10.1038/jid.2011.108
• 发表时间: 2011
• 期刊: The Journal of investigative dermatology
• 作者: Nousbeck,Janna;Ishida-Yamamoto,A;Bidder,Miri;Fuchs,Dana;Eckl,Katja;Hennies,HansChristian;Sagiv,Nadav;Gat,Andrea;Gini,Meri;Filip,Irina;Matz,Hagit;Goldberg,Ilan;Enk,ClaesD;Sarig,Ofer;Meilik,Benny;Aberdam,Daniel;Gilhar,Amos
• 通讯作者: Gilhar,Amos

Association of KIR Genes and MHC Class I Ligands with Atopic Dermatitis.

• DOI: 10.4049/jimmunol.2100379
• 发表时间: 2021-09-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Margolis DJ;Mitra N;Hoffstad OJ;Kim BS;Monos DS;Phillips EJ
• 通讯作者: Phillips EJ

Warm, humid, and high sun exposure climates are associated with poorly controlled eczema: PEER (Pediatric Eczema Elective Registry) cohort, 2004-2012.

• DOI: 10.1038/jid.2013.274
• 发表时间: 2014-01
• 期刊: JOURNAL OF INVESTIGATIVE DERMATOLOGY
• 影响因子: 6.5
• 作者: Sargen, Michael R.;Hoffstad, Ole;Margolis, David J.
• 通讯作者: Margolis, David J.

Persistence of mild to moderate atopic dermatitis.

• DOI: 10.1001/jamadermatol.2013.10271
• 发表时间: 2014-06
• 期刊: JAMA DERMATOLOGY
• 影响因子: 10.9
• 作者: Margolis, Jacob S.;Abuabara, Katrina;Bilker, Warren;Hoffstad, Ole;Margolis, David J.
• 通讯作者: Margolis, David J.