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

The role of the β2-adrenergic receptor (ADRB2) gene in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the association between ADRB2 variants and the risk of exacerbations in COPD patients treated with inhaled β2-agonists. Within the Rotterdam Study, a population-based cohort study, we followed 1053 COPD patients until the first COPD exacerbation or end of follow-up and extracted rs1042713 (16Arg > Gly) and rs1042714 (27Gln > Glu) in ADRB2. Exposure to inhaled β2-agonists was categorized into current, past, or non-use on the index date (date of COPD exacerbation for cases and on the same day of follow-up for controls). COPD exacerbations were defined as acute episodes of worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate exacerbations), or hospitalization (severe exacerbations). The associations between ADRB2 variants and COPD exacerbations were assessed using Cox proportional hazards models, adjusting for age, sex, use of inhaled corticosteroids, daily dose of β2-agonists, and smoking. In current users of β2-agonists, the risk of COPD exacerbation decreased by 30% (hazard ratio (HR); 0.70, 95% CI: 0.59–0.84) for each copy of the Arg allele of rs1042713 and by 20% (HR; 0.80, 95% CI: 0.69–0.94) for each copy of the Gln allele of rs1042714. Furthermore, current users carrying the Arg16/Gln27 haplotype had a significantly lower risk (HR; 0.70, 95% CI: 0.59–0.85) of COPD exacerbation compared to the Gly16/Glu27 haplotype. In conclusion, we observed that the Arg16/Gln27 haplotype in ADRB2 was associated with a reduced risk of COPD exacerbation in current users of inhaled β2-agonists.


Contents Supplemental methods 3
Baseline characteristics 3 Systematic review 3 Review criteria and data extraction 4

Supplemental results 4
Supplementary tables and figures 7 Table S1: Search strategy per library 7 Table S2: Functional annotation of rs1042713 using the HaploRegv4.1 8 Table S3: Functional annotation of rs1042714 using the HaploRegv4.1 9 Supplemental methods

Baseline characteristics
BMI was calculated as weight divided by height squared (kg/m 2 ). Diabetes mellitus was defined as a fasting serum glucose concentration of ≥7.0 mmol/L or a non-fasting serum glucose concentration of ≥11.1 mmol/L or the use of blood glucose-lowering medications [1]. Hypertension was defined as a resting blood pressure above 140/90 mmHg or the use of blood pressure-lowering medication. The diagnosis of heart failure was based on follow-up using the medical records of the participants [2].
Coronary Heart Diseases (CHD) was defined as a compound outcome including fatal or nonfatal myocardial infarction or CHD mortality [2].

Systematic review
We conducted an extensive electronic literature search of Embase, Medline Ovid, and Cochrane Central using multiple search terms (Supplementary Table S1) to identify all articles investigating ADRB2 polymorphisms; rs1042713 and/or rs1042714 and/or their haplotypes and COPD exacerbations in patients exposed to β 2 -agonists. Our literature search was restricted to studies published in English from inception until 30 September 2019.
Additional potentially relevant articles were searched through article reference lists.

Review criteria and data extraction
We considered all original articles, excluding conference abstracts, editorials, short surveys, and animal studies. We did not set any limits on study design, sample size, location, or follow-up. Studies were included if they met the following three criteria; (1) COPD patients exposed to inhaled short-acting β 2 -agonists (SABA) and/or long-acting β 2agonists (LABA) were eligible to be included in the review.
(2) The exposure variable of interest was ADRB2 polymorphisms; rs1042713 and/or rs1042714 and/or their haplotypes.

Supplemental results
The literature search yielded 369 hits, of which 270 unique articles remained after excluding duplicates. Of these 270 articles, the title and abstract were reviewed and 236 articles were excluded (conference abstracts (26), editorials (10), experimental studies (5), short surveys (5) and as they were unrelated to the association between ADRB2 polymorphisms and treatment response to inhaled β 2 -agonist in patient with COPD (190). We reviewed 34 fulltext articles and 27 of these were excluded for the following reasons; review article (13), letter (1), focus on other SNPs in ADRB2 (3), focus on different outcomes (10). In total, three clinical trials and four observational studies were withheld, but in the latter, not all of the included patients were on treatment with inhaled β 2 -agonist ( Figure S2).
Briefly, the three clinical trials that met inclusion criteria [3][4][5] were published between 2012 and 2014. The sample size ranged from 565 to 2,561. Two studies were multicentre, and another one was from the United States. One assessed the association between the SNPs and time to first COPD exacerbation using Kaplan-Meier curves and the log-rank test. [4] Rabe et al. found that patients with the Arg16Arg genotype and using salmeterol and inhaled corticosteroids (ICS) had a significantly lower risk of COPD exacerbations compared with Gly16Gly (p=0·0018) and Arg16Gly (p=0·0130) genotypes [4]. They found no significant differences in exacerbation risk between the genotypes of rs1042714. [4] Two other studies [3,5] assessed the association of the SNP(s) with the number of COPD exacerbations. One of them used Poisson regression to asses this association and while the other study described the distribution of the number of COPD exacerbation across the genotype categories of rs104213.
They found no significant association between the SNPs and COPD exacerbations in COPD patients using LABA [3,5].