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Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration is associated with high risks of asthma hospitalisation and exacerbation.We prospectively assessed the risk of asthma hospitalisation in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608 and rs448260 determining levels of complement C3. Risk of asthma exacerbation was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisation was 1.23 (95% CI 1.04-1.45) for individuals in the highest tertile (>1.19 g·L -1 ) of plasma complement C3 compared with those in the lowest tertile (<1.03 g·L -1 ). The C3 rs448260 genotype was associated with risk of asthma hospitalisation with an observed hazard ratio of 1.17 (95% CI 1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE (p for trends ≤6×10 -9 ), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count (p=3×10 -4 ) and IgE level (p=3×10 -4 ). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbation was 1.69 (95% CI 1.06-2.72) for individuals in the highest plasma complement C3 tertile (>1.24 g·L -1 ) versus the lowest (<1.06 g·L -1 ).In conclusion, a high concentration of plasma complement C3 was associated with a high risk of asthma hospitalisation in the general population and with a high risk of asthma exacerbation in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity., Competing Interests: Conflict of interest: S. Vedel-Krogh has nothing to disclose. Conflict of interest: K.L. Rasmussen has nothing to disclose. Conflict of interest: B.G. Nordestgaard has nothing to disclose. Conflict of interest: S.F. Nielsen has nothing to disclose., (Copyright ©ERS 2021.)

Blood eosinophil count in chronic obstructive pulmonary disease (COPD) is associated with higher exacerbation rate and favourable response to corticosteroids; however, frequent exacerbations and use of inhaled corticosteroids could elevate pneumonia risk. We tested the hypothesis that high blood eosinophil counts are associated with high risk of pneumonia in individuals with severe COPD from the general population.We included 7180 individuals with COPD from the Copenhagen General Population Study, including 643 with forced expiratory volume in 1 s (FEV 1 ) <50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded.Among individuals with COPD and FEV 1 <50% pred, the multivariable adjusted incidence rate ratio was 2.17 (95% CI 1.31-3.58) for pneumonia comparing individuals with blood eosinophil counts ≥0.34×10 9  cells·L -1 versus <0.34×10 9  cells·L -1 In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV 1 <70% pred, the corresponding risk was 4.52 (2.11-9.72). Risk of pneumonia did not differ by blood eosinophil count in individuals with COPD and FEV 1 ≥50% pred.In individuals with COPD and FEV 1 <50% pred, blood eosinophil count ≥0.34×10 9  cells·L -1 was associated with high risk of hospitalisation due to pneumonia., Competing Interests: Conflict of interest: J. Vestbo has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, GlaxoSmithKline and Novartis, outside the submitted work. Conflict of interest: P. Lange has received grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Novartis and GlaxoSmithKline, and personal fees from Norpharma, Takeda and Pfizer, outside the submitted work., (Copyright ©ERS 2018.)

Epigenome-wide association studies have shown a consistent association between smoking exposure and hypomethylation in the aryl hydrocarbon receptor repressor ( AHRR ) gene (cg05575921). We tested the hypothesis that AHRR hypomethylation is associated with low lung function, steeper lung function decline, and respiratory symptoms in the general population. AHRR methylation extent was measured in 9113 individuals from the 1991-1994 examination of the Copenhagen City Heart Study, using bisulfite-treated leukocyte DNA. Spirometry at the time of blood sampling was available for all individuals. Lung function was measured again for 4532 of these individuals in 2001-2003.Cross-sectionally, a 10% lower methylation extent was associated with a 0.2 z-score (95% CI 0.1-0.2) lower forced expiratory volume in 1 s (FEV 1 ) after multivariable adjustment including smoking. Hypomethylation was also associated with a lower z-score for both forced vital capacity (FVC) and FEV 1 /FVC. In prospective analyses, individuals in the lowest versus highest tertile of methylation extent had a steeper decline in FEV 1 /height 3 (p for examination×methylation interaction=0.003) and FVC/height 3 (p=0.01), but not FEV 1 /FVC (p=0.08). Multivariable-adjusted odds ratios per 10% lower methylation extent were 1.31 (95% CI 1.18-1.45) for chronic bronchitis and 1.21 (95% CI 1.13-1.30) for any respiratory symptoms. AHRR hypomethylation was associated with low lung function, steeper lung function decline, and respiratory symptoms., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)