β2-Adrenergic Receptor (ADRB2) Gene Polymorphisms and Risk of COPD Exacerbations: The Rotterdam Study

Karimi, Leila; Lahousse, Lies; Ghanbari, Mohsen; Terzikhan, Natalie; Uitterlinden, André G.; Lei, Johan van der; Brusselle, Guy; Stricker, Bruno H.; Verhamme, Katia

doi:10.3390/jcm8111835

Cited by 17 publications

(15 citation statements)

References 28 publications

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“…Also, asthma treatment policy that affects doctors’ underlying tendencies to prescribe OCS varies in different countries, which in turn could influence the proportion of asthma exacerbations 38 . In all studies, both SNPs were in complete linkage disequilibrium (D’~1) with each other; as a result, we determined three haplotypes of the four possible haplotypes (Arg16/Gln27 was not reported), which is in line with previous findings 39,40 . Furthermore, considering ethnicity variability in our study populations, we observed different minor allele frequencies in each SNP that resulted in considerable variations in r 2 , which indicates the correlation coefficient of the allele frequencies.…”

Section: Discussionsupporting

confidence: 85%

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta‐analysis

Karimi

Vijverberg

Engelkes

et al. 2021

Clin Experimental Allergy

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Background The polymorphism Arg16 in β2‐adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long‐acting β2‐agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi‐ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma‐related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta‐analysed using the inverse variance weighting method assuming random‐effects. Results In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as‐required short‐acting β2‐agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype‐guided treatment which might improve clinical outcomes in asthmatic patients.

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Section: Discussionsupporting

confidence: 85%

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta‐analysis

Karimi

Vijverberg

Engelkes

et al. 2021

Clin Experimental Allergy

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“…Hussein et al revealed an association of the Arg16 genotypes with highly pronounced respiratory symptoms and frequent exacerbations in Egyptian patients with COPD, and these findings were consistent with our data. However, a recent study by Karimi et al identified that Arg16/Gln27 haplotype reduces the risk of COPD exacerbation in patients using beta‐2‐agonists. The contradictory relationship between genetic variants of ADRB2 and the predisposition to asthma and COPD could be because each of these diseases includes common and specific endotypes and phenotypes, where the alleles of various genes make different contributions .…”

Section: Discussionmentioning

confidence: 98%

An investigation of the association between ADRB2 gene polymorphisms and asthma in Kazakh population

Akparova

Aripova

Abishev³

et al. 2020

Clinical Respiratory J

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Introduction: Beta-2-adrenergic receptor (ADRB2) is present in the cells of the respiratory tract, including bronchial smooth muscle cells and bronchial epithelium, and is a target for endogenous catecholamines and drugs used to treat the obstructive lung diseases. Objectives: This study aimed to investigate the possible association of the Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene with asthma and its endophenotypes in the Kazakh population. Methods: A total of 70 asthmatic patients and 80 healthy controls were genotyped for Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene by using quantitative real-time polymerase chain reaction. Statistical analysis was performed with the Graph Pad InStat 7 Software. Results: No associations between the asthma patients and healthy individuals were found when the allele and genotype distribution of Arg16Gly and Gln27Glu single nucleotide polymorphisms were compared. Analysis of the haplotype frequencies showed statistically significant differences between patients with asthma and controls for Arg16Gly/Gln27Gln and Arg16Gly/Gln27Glu haplotypes (odds ratio [OR] = 2.12, 95% confidence interval [CI] = 0.87-5.16 and OR = 2.25, 95% CI = 0.89-5.67 respectively). The Arg16 allele and Arg16Arg genotype frequencies were higher in patients with uncontrolled asthma than in controls (χ 2 = 5.17, df = 1, P = 0.02 and χ 2 = 5.36, df = 1, P = 0.02 respectively). Conclusion:The results of this study support the possible involvement of Arg16Gly polymorphism in the development of uncontrolled asthma, and indicate that Arg16Gly/Gln27Gln and Arg16Gly/Gln27Glu haplotypes are more common in asthma patients in the Kazakh population. K E Y W O R D Sasthma, beta-2-adrenergic receptor, Kazakhstan, single nucleotide polymorphisms

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“…January 1, 2011), whichever came first. COPD exacerbations were defined as acute episodes of worsening of respiratory symptoms requiring use of either systemic corticosteroids and/or antibiotics (moderate exacerbations), or requiring hospitalisation (severe exacerbations) [ 22 , 23 ]. The outcome was defined as the first moderate to severe COPD exacerbation during follow-up and the date of outcome was taken as the index date.…”

Section: Methodsmentioning

confidence: 99%

Effect of β-blockers on the risk of COPD exacerbations according to indication of use: the Rotterdam Study

et al. 2021

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Observational studies report a reduction of COPD exacerbations in patients treated with β-blockers. In contrast, the BLOCK COPD RCT which excluded COPD patients with cardiovascular (CV) conditions showed an increase in COPD exacerbations. It is unclear whether this discrepancy could be explained by underlying CV comorbidity. We examined whether the association between use of β-blockers and risk of COPD exacerbations differed between patients with and without a CV indication for β-blockers use.Within the Rotterdam Study, we followed COPD subjects until the first COPD exacerbation, or end of follow-up. Cardiovascular indication for β-blocker use was defined as a history of hypertension, coronary heart disease, atrial fibrillation, or heart failure at baseline. The association between β-blockers use and COPD exacerbations was assessed using Cox proportional hazards models adjusted for age, sex, smoking, incident CV disease (i.e., heart failure, hypertension, atrial fibrillation, and coronary heart disease during follow-up), respiratory drugs, and nitrates.In total 1312 COPD patients with a mean age=69.7±9.2 years were included. In patients with a CV indication (n=755, mean age=70.4±8.8 years), current use of cardioselective β-blockers was significantly associated with a reduced risk of COPD exacerbations (HR=0.69, 95% CI: 0.57–0.85). In contrast, in subjects without a CV indication (n=557, mean age=68.8±9.7 years), cardioselective β-blockers was not associated with an altered risk of COPD exacerbations (HR=0.94, 95% CI: 0.55–1.62).Use of cardioselective β-blockers reduced the risk of exacerbations in COPD patients with concomitant cardiovascular diseases. Therefore, the potential benefits of β-blockers might be confined to COPD patients with cardiovascular disease.

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β2-Adrenergic Receptor (ADRB2) Gene Polymorphisms and Risk of COPD Exacerbations: The Rotterdam Study

Cited by 17 publications

References 28 publications

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta‐analysis

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta‐analysis

An investigation of the association between ADRB2 gene polymorphisms and asthma in Kazakh population

Effect of β-blockers on the risk of COPD exacerbations according to indication of use: the Rotterdam Study

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