β₂-Adrenergic genotypes and risk of severe exacerbations in COPD: a prospective cohort study

Abstract

BackgroundIndividual 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.MethodsAmong 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.ResultsWe 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.ConclusionCommon β2-adrenergic receptor genotypes influence risk of severe exacerbations in COPD, potentially mainly by genetic influence of the 16Arg allele in rs1042713.

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

“…The results of the study showed an increased risk of COPD exacerbations in carriers of Arg16 and Gln27 [20]. However, the proportion of COPD patients treated with LABA from the Copenhagen General Population Study was low (9.8%) [20] particularly in comparison to our finding that revealed a protective effect in the category of current users of inhaled β 2 -agonists. So far, a few studies have examined the association between ADRB2 haplotypes and response to β 2 -agonist [9,21,23].…”

“…A recent observational study, in spirometry-confirmed COPD patients, examined the associations between ADRB2 polymorphisms (Arg16Gly and Gln27Glu) and risk of severe COPD exacerbations. [20]. The results of the study showed an increased risk of COPD exacerbations in carriers of Arg16 and Gln27 [20].…”

“…To summarize, a number of studies have assessed the effect of ADRB2 polymorphisms on treatment response to β 2 -agonists with inconsistent results [5,6,7,8,9,20,21,22,23,24,25]. Variation in the results might be related to differences in the study populations, study designs, ethnicity, outcome definitions, treatment classifications, concomitant drugs, as well as power-related issues due to different sample sizes.…”

β2 adrenergic receptor polymorphisms and COPD exacerbations: a complicated story

“…In this issue of Thorax , using data from individuals with COPD in the Copenhagen General Population Study (n=5,262) and the Copenhagen City Heart Study (n=923), Ingebrigtsen et al tested the association of β2 adrenergic receptor polymorphisms Gly16Arg (rs1042713, c.46G>A) and Gln27Glu (rs1042714, c.79C>G) with incident risk of COPD exacerbations requiring hospitalization 10 . In the Copenhagen General Population Study, compared to 16Gly homozygotes, 16Gly/Arg heterozygotes (hazards ratio [HR] 1.62, 95% confidence intervals [CI] 1.30-2.03, p=0.00002) and 16Arg homozygotes (HR 1.41, 95% CI 1.04-1.91, p=0.03) were more likely to experience severe COPD exacerbations.…”

“…Furthermore, the findings of this study could potentially impact a large number of individuals with COPD given the high prevalence of the studied β2 adrenergic receptor polymorphisms. For comparison, while it is estimated that fewer than 10% of COPD patients carry the Pi*Z allele variant in the SERPINA1 gene associated with alpha-1 anti-trypsin deficiency 12 , more than 60% are carriers of the 16Arg allele in rs1042713 8–10 .…”