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Publications

Journal Article Ahead of print

PubMed: 41352569 DOI: 10.1016/j.rmed.2025.108553

Variants in the Glucocorticoid Receptor gene (NR3C1), asthma control and serum cytokine levels.

Respir Med

Authors: Maria Borges Rabêlo de Santana, Álvaro A Cruz, João Locke Ferreira de Araújo, Rafaela Machado Tugores, Helena Mariana Pitangueira Teixeira, Talita Santos de Jesus, Gabriela Pimentel, Cinthia Vila Nova Santana, Nazanin Zounemat Kermani, Kian Fan Chung, Ian M Adcock, Adelmir Souza-Machado, Camila Alexandrina Figueiredo, Ryan Dos Santos Costa

Affiliations

  • Departamento de Biorregulação, Laboratório de Imunofarmacologia e Biologia Molecular, Universidade Federal da Bahia (ICS), Bahia-Brasil.
  • Fundação PROAR e Faculdade de Medicina da Universidade Federal da Bahia, Salvador, Bahia, Brazil.
  • Department of National Heart and Lung Institute, Imperial College London, London, United Kingdom.
  • Departamento de Biorregulação, Laboratório de Imunofarmacologia e Biologia Molecular, Universidade Federal da Bahia (ICS), Bahia-Brasil.

Abstract

INTRODUCTION

Asthma is a heterogeneous disease usually treated with inhaled corticosteroids (ICS) and long-acting beta2 agonists. However, not all individuals achieve adequate control with ICS.

AIM

To identify genetic variants in the glucocorticoid receptor gene (NR3C1) associated with asthma endophenotypes, bronchodilator reversibility, and asthma control under medium-to-high ICS doses.

METHODS

Association analyses were performed in 365 patients with moderate-to-severe asthma, 383 with mild asthma, and 330 non-asthmatic individuals. Asthma severity was defined by the need for regular treatment with medium-to-high ICS doses. Bronchodilator reversibility was defined as an increase of ≥200 ml and ≥12% in FEV1 from baseline. Asthma control was assessed using the ACQ6 score. Serum cytokine concentrations were measured with Luminex.

RESULTS

The A allele of rs2918417 was associated with reduced risk of moderate-to-severe asthma (OR: 0.50; 95% CI: 0.26-0.98) and fewer exacerbations (OR: 0.54; 95% CI: 0.30-0.96); GA/AA genotypes showed lower IL-8 and IL-13 levels compared to GG. The G allele of rs6877893 decreased the risk of uncontrolled asthma in the recessive model (OR: 0.53; 95% CI: 0.29-0.98), with GG carriers showing reduced IL-17A. Conversely, the A allele of rs4585488 increased risk of uncontrolled asthma (OR: 4.42; 95% CI: 1.06-18.48), and the C allele of rs4912650 was linked to poor control (OR: 1.64; 95% CI: 1.01-2.69). The G allele of rs4607376 was associated with lack of bronchodilator reversibility (OR: 1.51; 95% CI: 1.05-2.17) and asthma exacerbations (OR: 1.37; 95% CI: 1.01-1.87).

CONCLUSIONS

NR3C1 variants are associated with moderate-to-severe asthma, poor control, lack of bronchodilator reversibility, and differential cytokine profiles.

MeSH

Cytokines, Genes, Glucocorticoids, Bronchodilator Agents, Serum, Receptors, Glucocorticoid, Alleles, Asthma