Identifying Genetic Determinants of Atopic Dermatitis and Bacterial Colonization Using Whole Genome Sequencing

L30 Identifying Genetic Determinants of Atopic Dermatitis and Bacterial Colonization Using Whole Genome Sequencing Rasika A. Mathias, ScD, Sameer Chavan, MS, Kruthika R. Iyer, Nicholas M. Rafaels, Meher Boorgula, Joseph Potee, Jon M. Hanifin, MD FAAAAI, Amy Paller, MD, Lynda C. Schneider, MD FAAAAI, Richard L. Gallo, MD PhD, Emma Guttman-Yassky, MD PhD, Peck Y. Ong, MD FAAAAI, Ingo Ruczinski, PhD, Terri H. Beaty, PhD, Li Gao, MD PhD, Lisa A. Beck, MD FAAAAI, Donald Y. M. Leung, MD PhD FAAAAI, Kathleen C. Barnes, PhD FAAAAI; Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, Oregon Health & Science University, Portland, OR, Northwestern University Feinberg School of Medicine, Chicago, IL, Boston Children’s Hospital, Boston, MA, Division of Dermatology, University of California, San Diego, San Diego, CA, Mount Sinai School of Medicine, New York, NY, Children’s Hospital Los Angeles, Los Angeles, CA, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, University of Rochester Medical Center, Rochester, NY, National Jewish Health, Denver, CO. RATIONALE: The genetic basis of S. aureus colonization in atopic dermatitis (AD) is unknown. To extend prior studies in this field, we have implemented the first whole genome sequencing (WGS) study to identify genetic determinants associated with risk of AD and bacterial colonization. METHODS: DeepWGS (;30x) was performed on 248 AD subjects with S. aureus colonization, 245 AD subjects without S. aureus and 237 nonatopic controls. Herewe present an initial analysis focused on single nucleotide variants (SNVs) in the Epidermal Differentiation Complex (EDC; chr1:151972910-153642037), a region rich in genes important for epidermal maturation. RESULTS: We identified 17,231 SNVs, of which 47% have never been observed in public catalogs of human variation. Fourteen SNVs had a p <0.001 comparing all AD to non-atopic controls, including missense variants in the genes encoding repetin (RPTN; p50.0005, OR50.53) an extracellular epidermal matrix protein, and late cornified envelope 1B (LCE1B, p50.0002, OR50.29). Both variants are strongly protective against AD; rs72696940 predicted to be ‘probably damaging’ is common (frequency513%) while rs56056379 predicted to be ‘benign’ is rare (frequency53%), respectively. Only modest evidence was found for associations with bacterial colonization among AD subjects. CONCLUSIONS: We use the EDC to showcase the potential of WGS to identify novel genetic determinants of AD. While our evidence for risk of bacterial colonization is less striking in the EDC, extensive analysis is underway to include SNVs across the genome, insertion/deletions and gene-level tests. We anticipate discovery of additional novel loci, and expect improved fine-mapping results in recognized genes in our expanded analysis.