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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: Genome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined.Objectives: We aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline.Methods: We analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1 and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts.Results: The 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10-16 for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts.Conclusions: Previously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries. [ABSTRACT FROM AUTHOR]

Background Despite its important role in many serious diseases, the genetic background for plasma YKL-40 has still not been systematically catalogued. Therefore, we aimed at identifying genetic variants in CHI3L1 influencing plasma YKL-40 levels in the general population. Methods We resequenced the promoter, all 10 exons and exon-flanking intron segments of CHI3L1 in 904 individuals from the Danish general population (n=8899) with extreme plasma YKL-40 levels, adjusted for age. To potentially identify clinically important genetic variants with elevated plasma YKL-40 levels, we included twice as many individuals with the highest plasma YKL-40 levels (n=603) compared with the lowest plasma YKL-40 levels (n=301). Next, we mapped linkage disequilibrium for all variants with a minor allele frequency (MAF) >0.005. Finally, all participants were genotyped for eight variants that had divergent MAFs in the two extreme plasma YKL-40 groups. Results We identified 59 genetic variants in CHI3L1. Fifteen of the genetic variants were associated with plasma YKL-40 levels. Three promoter SNPs, 1 nonsynonymous SNP, and four intronic SNPs in CHI3L1 were associated with plasma YKL-40 levels at or below genome-wide association significance levels (unadjusted p for trend: from 4 × 10-8 to 6 × 10-243; age adjusted percentiles p for trend: from 3 × 10-12 to 2 × 10-304). Conclusions In a systematic search to identify genetic variants influencing plasma YKL-40 levels, we identified eight SNPs associated with plasma YKL-40 levels in the general population. [ABSTRACT FROM AUTHOR]

The article presents a study that used the mendelian randomisation approach in determining the association between genetically low 25-hydroxyvitamin D concentrations and increased mortality in white participants of Danish descent. The results of the study showed that low vitamin D concentrations increased all cause mortality, including cancer mortality, but not cardiovascular mortality. Also mentioned is the impact of sun exposure and skin colour on 25-hydroxyvitamin D concentrations.

Background It is unclear whether elevated plasma C reactive protein (CRP) is causally related to chronic obstructive pulmonary disease (COPD). The authors tested the hypothesis that genetically elevated plasma CRP causes COPD using a Mendelian randomisation design. Methods The authors measured high-sensitivity CRP in plasma, genotyped for four single nucleotide polymorphisms in the CRP gene, and screened for spirometry-defined COPD and hospitalisation due to COPD in 7974 individuals from the Copenhagen City Heart Study and in 32?652 individuals from the Copenhagen General Population Study. Results Elevated plasma CRP >3⇔…mg/l compared with <1⇔…mg/l was associated with risk estimates of 1.8 and 2.8 for spirometry-based COPD and of 1.6 and 1.8 for hospitalisation due to COPD in the Copenhagen City Heart Study and the Copenhagen General Population Study, respectively. Genotype combinations of the four CRP polymorphisms were associated with up to a 62% increase in plasma CRP. However, these genotype combinations did not associate with increased risk of COPD or hospitalisation due to COPD in either cohort or in the two cohorts combined. On instrumental variable analysis, a doubling of plasma CRP versus a doubling of genetically elevated CRP resulted in ORs for COPD of 1.27 (95% CI 1.25 to 1.30) versus 1.01 (0.81 to 1.26) and for COPD hospitalisation of 1.47 (1.43 to 1.51) versus 0.82(0.59 to 1.13). Conclusion Although elevated CRP is related to both a diagnosis of COPD and subsequent hospital admission, genetically elevated plasma CRP is not associated with an increased risk of clinical COPD. This suggests that the association between CRP levels and COPD is not causal. [ABSTRACT FROM AUTHOR]