Polymorphisms of the beta2-adrenergic receptor in COPD in association with disease severity

Introduction:

Although COPD is not a disease which is coupled to a single gene defect rather being a disease based on numerous grounds various gene polymorphisms have been found and linked to the development and disease severity of COPD. The ß₂-adrenergic receptor is a positional candidate gene for asthma and possible also for COPD, located on 5q31–33. There are 9 known polymorphisms in this gene whereas the ADRB2 haplotype allele and the Arg(16) polymorphism appears to be important in determining the agonist drug response. Other studies suggest a gene-environment interaction between the Arg-16 genotype and ever cigarette smoking with respect to the susceptibility of an individual to asthma. In some studies the Gly(16) alllele ahs associated with increased bronchial hyper-responsiveness (BHR), body-mass-index (BMI) and asthma severity. In COPD-patients heterozygosity at position 27 (Gln27 → Glu) may even be protective against an accelerated rate of decline in lung function.

The aim of this study was to investigate if possible ß₂-adrenergic receptor gene polymorphisms can be linked to COPD phenotype.

Methods:

We analyzed 190 COPD patients (GOLD 0–1, 2–4). About half of them were in stable conditions while the other half had more severe disease stage and suffer from frequent exacerbations (≥ 3 hospitalizations within the last 3 years). The COPD group was compared with patients without any pulmonary disease (control, n=132). From EDTA whole blood (18ml) DNA was isolated, and the frequency of two of gene polymorphism of the ß2-receptor gene was analyzed: Arg 16/Gly und Gln27/Glu. Furthermore smoking history, disease development according to the patients reports, lung function and blood gas analysis were recorded.

Results:

ARG16/Arg was found in COPD patients less frequent than in healthy smokers (18% COPD vs. 23% controls, p<0,05). In contrast Gly 16/Gly was rare in the controls (17%) when compared with COPD (29%, p<0,01). A signifikant association between the Gln27 ß2-AR polymorphism and the severity of COPD, which was represented by values for FEV1 percent predicted, was observed (p<0,001). Differences between stable COPD patients and frequent exacerbators were seen only as a trend. According to the patient selection lung function (FEV1) was best in the control group and worst in patients with frequent exacerbations.

Summary:

Our results hint that ß2-receptor gene polymorphism may be involved in COPD development, eventually contributing to individual susceptibility.