Polymorphisms in ADRB2 gene can modulate the response to bronchodilators and the severity of cystic fibrosis

Abstract

Background: The most common cystic fibrosis (CF) manifestation is the progressive chronic obstructive pulmonary disease caused by deficiency, dysfunction, or absence of the CFTR (Cystic Fibrosis Transmembrane Regulator) protein on the apical surface of the cells in the respiratory tract. The use of bronchodilators (BD), and inhaled corticosteroids (IC) have been suggested for the management of airway inflammation in CF. The effectiveness of BD and IC have been verified, proven in laboratory and in the clinical treatment for asthma patients. However, in CF, the effectiveness of these drugs is controversial. The extent of asthma's response to BD depends on the presence of polymorphisms in the ADRB2 gene. In contrast, in CF, little is known about the response to the BD and the association of CF´s severity with the different polymorphisms in ADRB2 gene. In this context, our objective was to verify whether the Arg16Gly and Glu27Gln polymorphisms in ADRB2 gene are associated with severity and with the bronchodilator response in CF patients.

Method: Cross-sectional study of 122 CF patients subjected to analysis of mutations in the CFTR gene, polymorphisms in ADRB2 gene, along with clinical and laboratorial characteristics of severity.

Result: The Arg16Gly polymorphism in ADRB2 gene was associated with pancreatic insufficiency(p:0.009), Bhalla score(p:0.039), forced expiratory volume in the first second[FEV1(%)](p:0.003), forced expiratory flow between 25 and 75% of the forced vital capacity-FVC[FEF25-75(%)](p:0.008) and lower age at the first isolation of the Pseudomonas aeruginosa(p:0.012). The response to the BD spirometry was associated with clinical severity markers, FEV1(%)(p:0.011) and FEF25-75(%)(p:0.019), for the Arg16Gly polymorphism in the ADRB2 gene. The haplotype analysis showed association with the FEV1/FVC marker from the spirometry test, before and after using the BD, with higher values in the group with Gly/Gly and Glu/Glu, respectively, for the Arg16Gly and Gln27Glu polymorphisms. The analysis by MDR2.0 software, showed association with FEF25-75%; the response to Arg16Gly was respondent by 17.35% and Gln27Glu by 6.8% in variation found.

Conclusion: There was an association between the Arg16Gly and Gln27Glu polymorphisms in ADRB2 gene with CF´s severity and bronchodilator response.

Figure 1

Bhalla score and spirometry values in Cystic Fibrosis patients modulated by polymorphism in ADRB2 gene. Association of the cystic fibrosis severity with polymorphism Arg16Gly in ADRB2 gene. A. Bloxplot of the Bhalla score in patients with two identified mutations in CFTR gene. The Bhalla score data is a gross value. # p:0.011; * p:0.779; ¥ p:0.007. B. Bloxplot of FEV₁(%) in patients without taking CFTR mutation into account. # p:0.007; * p:0.277; ¥ p:0.003. C. Bloxplot of FEF25-75% in patients without without taking CFTR mutation into account. # p:0.038; * p:0.43; ¥ p:0.015. D. Bloxplot of FEF25-75% in patients with no mutations identified in CFTR gene. # p:0.933; * p:0.008; ¥ p:0.001. The data of the spirometry are in percentage of the predicted population value. The test used for the analyses was the T´student test.

Figure 2

Bronchodilatador response in Cystic Fibrosis patients modulated by polymorphism in ADRB2 gene. Response to the inhaler bronchodilators by the alteration of spirometry markers values in the Cystic Fibrosis patients according to polymorphism Arg16Gly in ADRB2 gene. A. Bloxplot of the variation in the FEV₁(%) before and after using bronchodilators in patients without without taking CFTR mutation into account. # p:0.361; * p:0.001; ¥ p:0.002. B. Bloxplot with the variation in the FEF25-75(%) before and after using bronchodilators in patients without without taking CFTR mutation into account. # p:0.031; * p:0.026; ¥ p:0.01. Analysis made group by group by the T´student test. The data from the pulmonary function test are in percentage of the predicted population value.