Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment - 08/09/23

Doi : 10.1016/j.jaci.2023.05.021

Javier Perez-Garcia, PharmD ^a, Antonio Espuela-Ortiz, PhD ^a, José M. Hernández-Pérez, MD, PhD ^b,^c, Ruperto González-Pérez, MD, PhD ^d, Paloma Poza-Guedes, MD, PhD ^d, Elena Martin-Gonzalez, MSc ^a, Celeste Eng, BSc ^e, Olaia Sardón-Prado, MD, PhD ^f,^g, Elena Mederos-Luis, MD ^h, Paula Corcuera-Elosegui, MD, PhD ^f, Inmaculada Sánchez-Machín, MD, PhD ^h, Javier Korta-Murua, MD, PhD ^f, Jesús Villar, MD, PhD ^i,^j,^k, Esteban G. Burchard, MD, MPH ^e,^l, Fabian Lorenzo-Diaz, PhD ^a,^m,^⁎^{^{∗
Equal contribution as senior authors.}} , Maria Pino-Yanes, PhD ^a,^i,^n,^⁎^{^{∗
Equal contribution as senior authors.}}
^a Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain
^b Pulmonary Medicine Service, Hospital Universitario N.S de Candelaria, La Laguna, Tenerife, Spain
^c Pulmonary Medicine Section, Hospital Universitario de La Palma, La Palma, Spain
^d Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
^e Department of Medicine, University of California San Francisco (UCSF), San Francisco, Calif
^f Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain
^g Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain
^h Allergy Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
ⁱ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
^j Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
^k Li Ka Shing Knowledge Institute at the St. Michael’s Hospital, Toronto, Ontario, Canada
^l Department of Bioengineering and Therapeutic Sciences, University of California San Francisco (UCSF), San Francisco, Calif
^m Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain
ⁿ Instituto de Tecnologías Biomédicas, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain

^∗Corresponding author: Maria Pino-Yanes, PhD, or Fabian Lorenzo-Diaz, PhD, Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna, Apartado 456, La Laguna, 38200 Santa Cruz de Tenerife, Spain.Genomics and Health GroupDepartment of BiochemistryMicrobiologyCell Biologyand GeneticsUniversidad de La LagunaApartado 456La LagunaSanta Cruz de Tenerife38200Spain

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Abstract

Background

The 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.

Objective

We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response.

Methods

Saliva, 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 < P < 1 × 10⁻⁶ 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.

Results

Genes 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).

Conclusions

Genes 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.

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Key words : Airway microbiome, CEBP, gastroesophageal reflux disease, inhaled corticosteroids, mGWAS, NR3C1, NF-κB, obesity, smoking, trichostatin A

Abbreviations used : CEBP, GEMAS, GALA II, GERD, ICS, mbGWAS, mbQTL, NR3C1, NF-κB, PC, SNP, TSA

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Vol 152 - N° 3

P. 799 - settembre 2023 Ritorno al numero

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Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment - 08/09/23

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