Atopic dermatitis (AD) is a highly pruritic chronic episodic inflammatory skin disease that often presents between 3 and 6 months of age but may also present during later childhood or in adulthood. In the US, AD affects roughly 10-20% of all children of all races and ethnic groups. The highest prevalence of AD in the US is among African-Americans. The prevalence of AD is increasing worldwide and it is a major public health burden. The majority of children with AD will also develop asthma and seasonal allergies. From the recent Global Burden of Disease study, AD was among the top 50 most prevalent diseases worldwide and it had the second highest disability rank of all non-malignant skin diseases. Recent studies have established a strong association between loss-of-function mutations in filaggrin (FLG), a gene coding for a protein responsible for maintaining an intact skin barrier and AD. We have already demonstrated that these mutations are also associated with more persistent AD. However, these mutations are rarely noted in children of African ancestry. As a result, there is a gap in our knowledge with respect to the basic biology of AD in African-Americans. We recently found that mutations in filaggrin-2 (FLG2) are associated with persistence of AD in African-American children. We have also shown that genetic variation of the gene that codes thymic stromal lymphopoietin appears to modify the association of FLG with AD. The goals of this proposal are to comprehensively explore the association of FLG2 with AD in African-Americans, to better understand the association of thymic stromal lymphopoietin with the persistence of AD, and to explore how TSLP/FLG2 interact to create the phenotype of persistent AD. We will continue to focus on loss-of- function mutations in skin barrier genes using FLG as a model, a concept that was recently justified by a report that LOF may be a preferred pathway for adaptation to environmental stimuli. We plan to focus our studies on African-Americans. This proposal has two goals. The first goal is to better understand FLG2 loss-of-function mutations in African Americans. The second goal is to better understand TSLP variation and ultimately the interaction between TSLP and barrier dysfunction.

Public Health Relevance

Atopic dermatitis (AD) is a very itchy chronic lifelong skin disease that often begins in early childhood and persists into adulthood. Recent studies have discovered a defective gene in Europeans and Asians but this gene does not seem to be prevalent in African-Americans with AD. Our goal is to explore other genes in order to better understand the prognosis of this disease overtime.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR069062-04
Application #
9627927
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Cibotti, Ricardo
Project Start
2016-02-18
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Margolis, David J; Mitra, Nandita; Gochnauer, Heather et al. (2018) Uncommon Filaggrin Variants Are Associated with Persistent Atopic Dermatitis in African Americans. J Invest Dermatol 138:1501-1506