Background Individual susceptibility to exacerbations in chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors; however, most such variance is unexplained. We hypothesised that β2-adrenergic receptor genotypes, Gly16Arg (rs1042713, c.46G>A) and Gln27Glu (rs1042714, c.79C>G) influence risk of severe exacerbations in COPD.
Methods Among 96 762 individuals in the Copenhagen General Population Study, we identified 5262 with COPD (forced expiratory volume in one second divided by forced vital capacity, FEV1/FVC, below 0.7, FEV1 less than 80% of predicted value, age above 40 years and no asthma) who had genotyping performed. Severe exacerbations were defined as acute admissions due to COPD during 5 years of follow-up (mean 3.4 years). 923 individuals with COPD diagnosed similarly in the Copenhagen City Heart Study (CCHS) were used for replication analyses.
Results We recorded 461 severe exacerbations in 5262 subjects. The HRs for severe exacerbations were 1.62 (95% CI 1.30 to 2.03, p=0.00002) for 16Gly/Arg heterozygotes and 1.41 (1.04 to 1.91, p=0.03) for 16Arg homozygotes, compared with 16Gly homozygotes. HRs were 1.35 (1.03 to 1.76, p=0.03) for 27Gln/Glu heterozygotes and 1.49 (1.12 to 1.98, p=0.006) for 27Gln homozygotes, compared with 27Glu homozygotes. Similar trends were observed in the CCHS. Among 27Gln homozygotes only, HRs were 5.20 (1.81 to 14.9, p=0.002) for 16Gly/Arg heterozygotes and 4.03 (1.40 to 11.6, p=0.01) for 16Arg homozygotes, compared with 16Gly homozygotes.
Conclusion Common β2-adrenergic receptor genotypes influence risk of severe exacerbations in COPD, potentially mainly by genetic influence of the 16Arg allele in rs1042713.
- adrenoreceptor polymorphisms
- precision medicine
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Contributors Study concept and design: TSI, JV, BGN, LR; acquisition of data: PL., BGN; analysis and interpretation of data: TSI, JLM, JV, BGN; critical revision of the manuscript: all authors; statistical analysis: TSI, JLM; obtained funding: PL, JV, BGN; study supervision: TSI, JV, BGN. All authors had full access to all the data in the study. TSI, BGN, and JLM take responsibility for the integrity of the data and the accuracy of the data analysis, and for the submission.
Funding Supported by the Capital Region of Copenhagen, the Danish Heart Foundation, the Danish Lung Foundation, the Velux Foundation, and Herlev and Gentofte Hospital. JV is supported by the NIHR Manchester Biomedical Research Centre.
Competing interests TSI has received a fee for speaking from AstraZeneca. JV has received honoraria from Chiesi, GlaxoSmithKline, Almirall, AstraZeneca, Boehringer-Ingelheim, and Novartis for consulting and for presenting at meetings and symposia, none of it related to the topic of this study. LR and JLM: none to declare. PL has received honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Teva, and GlaxoSmithKline for presenting at meetings and symposia, none of it related to the topic of this study. BGN: none to declare.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available.
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