1. Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment
- Author
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Perez-Garcia, Javier, Espuela-Ortiz, Antonio, Hernández-Pérez, José M, González-Pérez, Ruperto, Poza-Guedes, Paloma, Martin-Gonzalez, Elena, Eng, Celeste, Sardón-Prado, Olaia, Mederos-Luis, Elena, Corcuera-Elosegui, Paula, Sánchez-Machín, Inmaculada, Korta-Murua, Javier, Villar, Jesús, Burchard, Esteban G, Lorenzo-Diaz, Fabian, and Pino-Yanes, Maria
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Microbiome ,Genetics ,Minority Health ,Human Genome ,Asthma ,Lung ,Health Disparities ,Respiratory ,Humans ,Anti-Asthmatic Agents ,Genome-Wide Association Study ,NF-kappa B ,Administration ,Inhalation ,Adrenal Cortex Hormones ,Human Genetics ,Cytidine Deaminase ,Minor Histocompatibility Antigens ,Carrier Proteins ,Gene -set enrichment analyses ,therapeutic drug ,Airway microbiome ,CEBP ,NF-κB ,NR3C1 ,gastroesophageal reflux disease ,inhaled corticosteroids ,mGWAS ,obesity ,smoking ,trichostatin A ,Allergy - Abstract
BackgroundThe upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown.ObjectiveWe sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response.MethodsSaliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 -6 were examined in gene-set enrichment analyses. Significant results were sought for replication in 114 African American and 158 Latino children with and without asthma. ICS-response-associated single nucleotide polymorphisms reported in the literature were evaluated as microbiome quantitative trait loci. Multiple comparisons were adjusted by the false discovery rate.ResultsGenes associated with exacerbation-related airway-microbiome traits were enriched in asthma comorbidities development (ie, reflux esophagitis, obesity, and smoking), and were likely regulated by trichostatin A and the nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein transcription factors (7.8 × 10-13 ≤ false discovery rate ≤ 0.022). Enrichment in smoking, trichostatin A, nuclear factor-κB, and glucocorticosteroid receptor were replicated in the saliva samples from diverse populations (4.42 × 10-9 ≤ P ≤ .008). The ICS-response-associated single nucleotide polymorphisms rs5995653 (APOBEC3B-APOBEC3C), rs6467778 (TRIM24), and rs5752429 (TPST2) were identified as microbiome quantitative trait loci of Streptococcus, Tannerella, and Campylobacter in the upper airway (0.027 ≤ false discovery rate ≤ 0.050).ConclusionsGenes associated with asthma exacerbation-related microbiome traits might influence asthma comorbidities. We reinforced the therapeutic interest of trichostatin A, nuclear factor-κB, the glucocorticosteroid receptor, and CCAAT/enhancer-binding protein in asthma exacerbations.
- Published
- 2023