Filaggrin Mutations and the Prognosis of Atopic Dermatitis

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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.