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Variants in the Glucocorticoid Receptor gene (NR3C1), asthma control and serum cytokine levels
Maria Borges Rabêlo de Santana1, Álvaro A Cruz2, João Locke Ferreira de Araújo1
1Departamento de Biorregulação, Laboratório de Imunofarmacologia e Biologia Molecular, Universidade Federal da Bahia (ICS), Bahia, Brazil.
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.
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