Chih-Yung Chiu1,2, Gigin Lin2,3, Chia-Jung Wang1, Shuen-Iu Hung4, Wen-Hung Chung5. 1. Department of Pediatrics, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan. 2. Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan. 3. Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan. 4. Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. 5. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan.
Abstract
BACKGROUND: Filaggrin (FLG) gene mutation and immunoglobulin E (IgE)-mediated sensitization are the most important predictors of atopic dermatitis (AD). However, a metabolomics-based approach to address the metabolic impact of FLG mutations on allergic IgE responses for AD is still lacking. We, though, determine the relationships of metabolic profiles in AD with FLG mutations and allergic responses. METHODS: Eighty-one children with adolescent AD (n = 58) and healthy controls (n = 23) were prospectively enrolled. Mutations in the filaggrin gene were identified using whole-exome sequencing, and plasma metabolic profiles were determined using 1 H-nuclear magnetic resonance (NMR) spectroscopy. Integrative analyses of their associations related to total serum IgE levels were performed, and further metabolic functional pathways for AD were also assessed. RESULTS: Metabolites contributed to the separation between AD and controls were identified using the supervised partial least squares discriminant analysis (Q2 /R2 = 0.90, Ppermutation <0.001). Nitrogen and amino acid metabolisms for energy production, and microbe-related methane and propanoate metabolisms were significantly associated with AD compared with healthy controls (FDR-adjusted p < .05). Five of fifteen metabolites related to FLG mutations were positively correlated with total serum IgE levels. Among them, dimethylamine and isopropanol were strongly associated with methane metabolism and propanoate metabolism, respectively, in AD with FLG mutations (FDR-adjusted p < .01). CONCLUSION: A strong correlation of microbial-derived metabolites, dimethylamine and isopropanol, with FLG mutations and IgE allergic reactions provides the influence of host genetics on the microbiome to regulate susceptibility to allergic responses in the pathogenesis of AD.
BACKGROUND: Filaggrin (FLG) gene mutation and immunoglobulin E (IgE)-mediated sensitization are the most important predictors of atopic dermatitis (AD). However, a metabolomics-based approach to address the metabolic impact of FLG mutations on allergic IgE responses for AD is still lacking. We, though, determine the relationships of metabolic profiles in AD with FLG mutations and allergic responses. METHODS: Eighty-one children with adolescent AD (n = 58) and healthy controls (n = 23) were prospectively enrolled. Mutations in the filaggrin gene were identified using whole-exome sequencing, and plasma metabolic profiles were determined using 1 H-nuclear magnetic resonance (NMR) spectroscopy. Integrative analyses of their associations related to total serum IgE levels were performed, and further metabolic functional pathways for AD were also assessed. RESULTS: Metabolites contributed to the separation between AD and controls were identified using the supervised partial least squares discriminant analysis (Q2 /R2 = 0.90, Ppermutation <0.001). Nitrogen and amino acid metabolisms for energy production, and microbe-related methane and propanoate metabolisms were significantly associated with AD compared with healthy controls (FDR-adjusted p < .05). Five of fifteen metabolites related to FLG mutations were positively correlated with total serum IgE levels. Among them, dimethylamine and isopropanol were strongly associated with methane metabolism and propanoate metabolism, respectively, in AD with FLG mutations (FDR-adjusted p < .01). CONCLUSION: A strong correlation of microbial-derived metabolites, dimethylamine and isopropanol, with FLG mutations and IgE allergic reactions provides the influence of host genetics on the microbiome to regulate susceptibility to allergic responses in the pathogenesis of AD.