In a study on human genetics and biological pathways that regulate airway microbiome traits associated with asthma exacerbations, researchers found trichostatin A, nuclear factor kB (NF-κB), a glucocorticosteroid receptor, and CCAAT/enhancer-binding protein (CEBP) transcription factors may influence asthma comorbidities, including reflux, esophagitis, and smoking.
“We hypothesize that host genetics regulate the upper-airway microbiome diversity and composition involved in asthma exacerbations and ICS [inhaled corticosteroid] response,” wrote the researchers of the study. “This study aimed to identify genetic variants and biological pathways regulating airway microbiome traits involved in asthma exacerbations despite ICS treatment.”
The full study is published in The Journal of Allergy and Clinical Immunology.
A total of 257 patients with asthma were included in the study; they were recruited from 2006 to 2014, and 257 saliva, 232 pharyngeal, and 229 nasal samples were collected. Using microbiome genome-wide association studies (mbGWAS), the researchers tested 6,296,951 genetic variants with exacerbation-related microbiome traits, despite ICS treatment. Variants with 1 x 10–4 < P < 1 x 10–6 were evaluated using gene-set enrichment analysis.
Any significant results were tested for replication in 114 African American and 158 Latino children with and without asthma. ICS response–associated single nucleotide polymorphisms were evaluated as microbiome quantitative trait loci, and multiple comparisons were adjusted by the false discovery rate. Patient demographics and clinical characteristics were collected as well.
Patients had a median age of 39 years, and 61.5% were female. Additionally, 88% of patients had severe persistent asthma and 25.8% had poorly controlled disease. Patients also reported gastroesophageal reflux disease (20.4%), obesity (31.7%), atopy (69.3%), recent antibiotic treatment (27.7%), and current smoking status (28.3%).
Twenty-four mbGWAS (P < 1 x 10–5) were identified for gene-set enrichment analysis. The researchers observed enrichment in genes previously associated with asthma comorbidities, including esophagitis, obesity, and smoking. Furthermore, genes associated in the mbGWAS partially overlapped with genes whose expression is regulated by trichostatin A and transcription factors, including the NF-κB; the glucocorticosteroid receptor, which was encoded by the NR3C1 genes; and CEBP.
Additionally, the researchers identified genetic loci at APOBEC3B-APOBEC3C, TRIM24, and TPST2 they believe may affect airway bacteria associated with asthma exacerbations and ICS response.
The researchers acknowledge some limitations to the study, such as a small sample size, which limited the ability to identify genome-wide significant associations; being unable to replicate results from the nasal and pharyngeal samples; and the inability to study the host genetic influence on specific bacterial species and microorganisms linked to asthma exacerbations and ICS response.
Despite these limitations, the researchers believe this study adds supporting evidence of TSA, NF-κB, the glucocorticosteroid receptor, and CEBP as significant genetic factors that should be considered in asthma treatment.
“In conclusion, genes suggestively associated with asthma exacerbation–related microbiome traits might have an influence on major asthma comorbidities development in diverse populations,” wrote the researchers. “Those genetic loci are significantly more likely to be regulated by TSA and NF-κB, [glucocorticosteroid receptor], and CEBP transcription factors than expected by chance."
Perez-Garcia J, Espuela-Ortiz A, Hernández-Pérez JM, et al. Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment. J Allergy Clin Immunol. Published online June 8, 2023. doi:10.1016/j.jaci.2023.05.021