David J Margolis1,2,3, Nandita Mitra1,2, Bradley Wubbenhorst1,4, Kurt D'Andrea1,4, Adam A Kraya1,4, Ole Hoffstad1,3, Saloni Shah1,3, Katherine L Nathanson1,4,5. 1. Perelman School of Medicine, University of Pennsylvania, Philadelphia. 2. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia. 3. Department of Dermatology, University of Pennsylvania, Philadelphia. 4. Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia. 5. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Abstract
IMPORTANCE: Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated. OBJECTIVES: To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD. DESIGN, SETTING, AND PARTICIPANTS: This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019. MAIN OUTCOMES AND MEASURES: Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD. RESULTS: A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80). CONCLUSIONS AND RELEVANCE: The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.
IMPORTANCE: Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated. OBJECTIVES: To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD. DESIGN, SETTING, AND PARTICIPANTS: This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019. MAIN OUTCOMES AND MEASURES: Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD. RESULTS: A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80). CONCLUSIONS AND RELEVANCE: The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.
Authors: David J Margolis; Nandita Mitra; Ron Berna; Ole Hoffstad; Brian S Kim; Albert Yan; Andrea L Zaenglein; Zelma Chiesa Fuxench; Ashley M Quiggle; Cristina de Guzman Strong; Xuan Fei Colin Cornelius Wong; John E Common Journal: J Dermatol Sci Date: 2020-01-31 Impact factor: 4.563