Background: Individual susceptibility to exacerbations in chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors; however, most such variance is unexplained. We hypothesized 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 5,262 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 forty years, and no asthma) who had genotyping performed. Severe exacerbations were defined as acute admissions due to COPD during five years of follow-up (mean 3.4 years). 923 individuals with COPD diagnosed similarly in the Copenhagen City Heart Study were used for replication analyses. Results: We recorded 461 severe exacerbations in 5,262 subjects. The hazard ratios for severe exacerbations were 1.62 (95% confidence interval, 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 to 16Gly homozygotes. Hazard ratios 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 to 27Glu homozygotes. Similar trends were observed in the Copenhagen City Heart Study. Among 27Gln homozygotes only, hazard ratios 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 to 16Gly homozygotes. Conclusion: Common β2-adrenergic receptor genotypes influence risk of severe exacerbations in COPD, possibly mainly by genetic influence of the 16Arg allele in rs1042713.
Ingebrigtsen, T. S., Vestbo, J., Rode, L., Marott, J. L., Lange, P., & Nordestgaard, B. G. (2019). β2-Adrenergic genotypes and risk of severe exacerbations in COPD: a prospective cohort study. Thorax, 74, 934-940. https://doi.org/10.1136/thoraxjnl-2018-212340