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Background: Vitamin D may regulate the innate immune system, and randomised controlled trials suggest a beneficial effect of vitamin D supplementation against acute respiratory tract infections. By using a Mendelian randomisation approach, we tested the hypothesis that low 25-hydroxyvitamin D is associated with increased risk of bacterial pneumonia in observational and genetic analyses.Methods: We genotyped 116 335 randomly chosen white Danes aged 20 to 100 from the Copenhagen City Heart Study and Copenhagen General Population Study for plasma 25-hydroxyvitamin D decreasing genetic variants around CYP2R1 (rs117913124, rs12794714 and rs10741657), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458) and HAL (rs3819817). Information on plasma 25-hydroxyvitamin D was available on 35 833 individuals. Individuals were followed from 1981 through 2018 for hospital diagnoses of bacterial pneumonias.Results: During up to 38 years follow-up, we observed 6342 bacterial pneumonias in observational analyses and 13 916 in genetic analyses. In observational analyses, multivariable adjusted HR for bacterial pneumonias was 1.27 (95% CI: 1.16 to 1.40) for individuals with 25-hydroxyvitamin D<25 nmol/L compared with those with ≥25 nmol/L. In genetic analyses, the OR for bacterial pneumonia per 10 nmol/L lower plasma 25-hydroxyvitamin D was 1.12 (95% CI: 1.02 to 1.23) in Wald's ratio, 1.12 (95% CI: 1.04 to 1.20) in inverse-variance weighted, 1.63 (95% CI: 0.96 to 2.78) in MR-Egger and 1.15 (95% CI: 1.05 to 1.26) in weighted median instrumental variable analysis. This association was strongest for genetic variants around CYP2R1. There was no observational or genetic evidence to support that 25-hydroxyvitamin D is associated with risk of urinary tract infections, skin infections, sepsis or gastroenteritis, which were used as negative control outcomes.Conclusions: Low vitamin D is associated observationally and genetically with increased risk of bacterial pneumonias. [ABSTRACT FROM AUTHOR]

Background: Urate is a strong antioxidant in plasma and may protect against lung function impairment. We tested the hypothesis that high plasma urate is causally associated with better lung function and low risk of respiratory symptoms and COPD.Methods: We measured lung function and plasma urate in 114 979 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and genotyped for SLC2A9 rs7442295 and ABCG2 rs2231142 variants, previously associated with high plasma urate, in 110 152 individuals.Results: In the two studies combined, multivariable-adjusted 100 µmol/L higher plasma urate was associated with -1.54% (95% CI -1.67 to -1.40) lower FEV1 % predicted and -1.57% (95% CI -1.69 to -1.44) lower FVC % predicted observationally; the corresponding estimates for genetically determined 100 µmol/L higher plasma urate were -0.46% (95% CI -1.17 to 0.25) and -0.40% (95% CI -1.03 to 0.23). High plasma urate was also associated with higher risk of respiratory symptoms; however, genetically determined high plasma urate was not associated with respiratory symptoms. Finally, we identified 14 151 individuals with COPD and found ORs of 1.08 (95% CI 1.06 to 1.11) for COPD observationally and 1.01 (95% CI 0.88 to 1.15) genetically per 100 µmol/L higher plasma urate.Conclusion: High plasma urate was associated with worse lung function and higher risk of respiratory symptoms and COPD in observational analyses; however, genetically high plasma urate was not associated with any of these outcomes. Thus, our data do not support a direct causal relationship. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the aryl hydrocarbon receptor repressor (AHRR) gene. We tested the hypothesis that AHRR cg05575921 hypomethylation is associated with risk of smoking-related morbidity and mortality.Methods: From the Copenhagen City Heart Study representing the Danish general population, we studied 9234 individuals. Using bisulphite treated leucocyte DNA, AHRR (cg05575921) methylation was measured. Rs1051730 (CHRN3A) genotype was used to evaluate smoking heaviness. Participants were followed for up to 22 years for exacerbations of COPD, event of lung cancer and all-cause mortality. Six-year lung cancer risk was calculated according to the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCOM2012).Measurements and Main Results: AHRR (cg05575921) hypomethylation was associated with former and current smoking status, high daily and cumulative smoking, short time since smoking cessation (all p values <7×10-31), and the smoking-related CHRN3A genotype (-0.48% per T-allele, p=0.002). The multifactorially adjusted HRs for the lowest versus highest methylation quintiles were 4.58 (95% CI 2.83 to 7.42) for COPD exacerbations, 4.87 (2.31 to 10.3) for lung cancer and 1.67 (1.48 to 1.88) for all-cause mortality. Finally, among 2576 high-risk smokers eligible for lung cancer screening by CT, observed cumulative incidences of lung cancer after 6 years for individuals in the lowest and highest methylation quintiles were 3.7% and 0.0% (p=2×10-7), whereas predicted PLCOM2012 6-year risks were similar (4.3% and 4.4%, p=0.77).Conclusion: AHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: A substantial proportion of individuals with airflow limitation are never-smokers. However, whether never-smokers with airflow limitation have undiagnosed asthma is unknown. We hypothesised that the majority of never-smokers with respiratory symptoms and airflow limitation but without known asthma have undiagnosed asthma by comparing characteristics and prognosis in never-smokers with airflow limitation and asthma (NS+AFL+A) with never-smokers with airflow limitation but without asthma (NS+AFL-A).Methods: Among 94 079 participants aged 20-100 years from the general population, 39 102 (42%) were never-smokers. In this group, 13 719 (35%) reported to have respiratory symptoms of whom 1610 (12%) had airflow limitation. We investigated characteristics and risk of complications (asthma or COPD exacerbations, pneumonias and all-cause mortality) and comorbidities (lung cancer, ischaemic heart disease, myocardial infarction, deep venous thrombosis and PE) during 4.5 years median follow-up.Results: NS+AFL-A compared with NS+AFL+A reported less allergy and respiratory symptoms, and had higher FEV1 and lower levels of eosinophils and IgE in peripheral blood. NS+AFL+A had increased risk of asthma and COPD exacerbations, but not of pneumonias; adjusted HRs in NS+AFL+A compared with NS+AFL-A were 16 (95% CI 3.7 to 73) for asthma exacerbations and 15 (2.8 to 80) for COPD exacerbations. Still, NS+AFL-A had increased risk of COPD exacerbations and pneumonias, but not of asthma exacerbations; adjusted HRs in NS+AFL-A compared with never-smokers without airflow limitation or asthma (NS-AFL-A) were 7.7 (2.8 to 21) for COPD exacerbations and 1.7 (1.3 to 2.3) for pneumonias. Risk of comorbidities or all-cause mortality was not increased in NS+AFL-A or NS+AFL+A compared with NS-AFL-A.Conclusions: Majority of NS+AFL-A do not seem to have undiagnosed asthma and may instead have airflow limitation caused by other risk factors. [ABSTRACT FROM AUTHOR]

Background: Observational studies suggest that obesity is associated with increased risk of asthma. However, it is unknown whether this could be explained by wheezing. We tested the hypothesis that high body mass index (BMI) observationally and genetically is associated with high risk of wheezing and asthma, and that the association between high BMI and asthma is explained by wheezing.Methods: We genotyped 85,437 individuals aged 20-100 years from the Copenhagen General Population Study for FTO (rs9939609), MC4R (rs17782313), TMEM18 (rs6548238) GNPDA2 (rs10938397) and BDNF (rs10767664); 14,500 individuals experienced wheezing and 5406 had asthma. Wheezing was self-reported, and asthma was ascertained through self-report, hospital contacts with asthma, and/or receiving medication for asthma. BMI was calculated as measured weight divided by measured height squared (kg/m2).Results: In observational analyses versus BMI of 18.5-22.4 kg/m2, ORs for wheezing were 1.23 (95% CI 1.00 to 1.52) for BMI <18.5 kg/m2, 1.17 (1.10 to 1.25) for 22.5-24.9 kg/m2, 1.44 (1.35 to 1.54) for 25-27.4 kg/m2, 1.86 (1.73 to 1.99) for 27.5-29.9 kg/m2, 2.48 (2.31 to 2.66) for 30-34.9 kg/m(2), 3.86 (3.48 to 4.28) for 35-39.9 kg/m2 and 6.05 (5.12 to 7.14) for BMI ≥40 kg/m2. Corresponding ORs for asthma were 1.28 (0.95 to 1.74), 1.07 (0.97 to 1.17), 1.14 (1.04 to 1.25), 1.32 (1.20 to 1.46), 1.39 (1.25 to 1.54), 1.54 (1.31 to 1.81) and 1.99 (1.55 to 2.56), respectively. Compared with BMI allele score 0-4, scores 5, 6 and 7-10 were associated with 0.22, 0.51 and 0.76 kg/m2 higher BMI, respectively. Genetically determined ORs per unit higher BMI were 1.22 (1.15 to 1.31) for wheezing, 1.18 (1.10 to 1.27) for wheezing without asthma, 1.08 (0.98 to 1.19) for asthma, and 0.85 (0.73 to 0.99) for asthma without wheezing. Corresponding observational ORs were 1.09 (1.09 to 1.10), 1.09 (1.08 to 1.09), 1.03 (1.03 to 1.04) and 0.99 (0.98 to 1.00), respectively.Conclusions: High BMI was associated with high risk of wheezing without asthma, but not with high risk of asthma without wheezing. [ABSTRACT FROM AUTHOR]