Estudo de varredura genômica para a resposta ao agonista β2 de curta ação em pacientes com asma

Abstract

Introduction: Asthma is usually characterized by chronic inflammation of the airways, whose obstruction can be reversible with the use of bronchodilators (BD). However, individuals with asthma do not respond to treatment, which can, at least in part, be explained by genetic variability. Objectives: To identify possible pharmacogenetic loci related to bronchodilator response (BDR) in a population with asthma. Methods: We performed a GWAS, with 716 individuals with asthma, to identify the variants associated with BDR, through the percentage variation of FEV1 after the use of albuterol. The variants were genotyped using a MEGA chip (Illumina) with subsequent imputation with the CAAPA (Consortium on Asthma among Populations of African Ancestry) reference panel. Pathway enrichment analyzes were performed using VEGAS2 and GARFIELD. Additionally, peripheral blood cytokine quantification was performed using Luminex technology and IL-10-producing regulatory T cells were evaluated by flow cytometry. Results: Twenty-six variants were suggestively associated (5x10-8<p-value<1x10-5) with BDR; three regions (PTPRC, PRKCH, and WWOX) were related using pathways-based analysis and are linked to immunological mechanisms. The independent signals in the rs3754098-T (OR (odds ratio):2.21, CI95% (confidence interval):1.57-3.12), (PTPRC), were associated with better BDR and higher levels of IL-10 in blood. The rs14095-G (OR:2.15, CI95%:1.60-2.87) (PRKCH); the rs76893638-T (OR:4.26, CI95%:2.43-7.47) (MYLIP); and rs7630434-C (OR:2.33, CI95%:1.67-3.27) (WWTR1) variants were associated with a better BDR, whereas rs2250772-C (OR:0.53, CI95%:0.40-0.70) (PRKCH) and rs75376533-C (OR:0.23, CI95%:0.13-0.42) (WWOX) were associated with a worse BDR. Among such regions, 2 variants located at WWTR1 and WWOX gene were replicated in Latinos from GALA II in the same direction as the discovery population. Conclusions: This work suggests that genes associated with immunological and physiological mechanisms may influence the bronchodilator response in patients with asthma. Our study expands the understanding of the pharmacogenetics of drug response in asthma, potentially providing new molecular targets associated with BDR and advances knowledge for precision medicine in asthma therapy in mixed populations such as Brazil.