Signe Vedel-Krogh

Blood Eosinophils and Exacerbations in Chronic Obstructive Pulmonary Disease. The Copenhagen General Population Study

RATIONALE Whether high blood eosinophils are associated with chronic obstructive pulmonary disease (COPD) exacerbations among individuals with COPD in the general population is largely unknown. OBJECTIVES To test the hypothesis that high blood eosinophils predict COPD exacerbations. METHODS Among 81,668 individuals in the Copenhagen General Population Study, we examined 7,225 with COPD based on spirometry. We recorded blood eosinophils at baseline and future COPD exacerbations longitudinally, defined as moderate (short-course treatment with systemic corticosteroids) or severe (hospitalization). We also assessed exacerbation risk in a subgroup of 203 individuals with clinical COPD, defined as participants with a smoking history of at least 10 pack-years, FEV1 less than 70% of predicted value, and at least one moderate or severe exacerbation in the year before baseline. MEASUREMENTS AND MAIN RESULTS During a median of 3.3 years of follow-up (range, 0.03-8.1), 1,439 severe and 2,864 moderate COPD exacerbations were recorded. Among all participants with COPD, blood eosinophils above versus below 0.34 × 10(9) cells per liter had multivariable-adjusted incidence rate ratios of 1.76 (95% confidence interval, 1.56-1.99) for severe exacerbations and 1.15 (1.05-1.27) for moderate exacerbations. Corresponding values in those with clinical COPD were 3.21 (2.49-4.14) and 1.69 (1.40-2.04). In contrast, using a cutpoint of 2% for blood eosinophils, the risk of exacerbations was increased for severe exacerbations only among individuals with clinical COPD and not in individuals in the broader population. CONCLUSIONS Among individuals with COPD in the general population, increased blood eosinophil levels above 0.34 × 10(9) cells per liter were associated with a 1.76-fold increased risk of severe exacerbations.

Association of blood eosinophil and blood neutrophil counts with asthma exacerbations in the copenhagen general population study

BACKGROUND Blood eosinophil count is a marker of eosinophilic airway inflammation and disease severity in asthma. However, blood neutrophil count might also be associated with disease severity. We tested the hypothesis that high blood eosinophil and neutrophil counts are both associated with the risk of asthma exacerbations among individuals with asthma from the general population. METHODS From the Copenhagen General Population Study with 81351 participants, we included 4838 with self-reported asthma. We recorded baseline blood eosinophil and neutrophil counts, and asthma exacerbations during follow-up in 2003-2011, defined as moderate (short-course treatment of prednisolone) or severe (hospitalization). RESULTS The multivariable-adjusted incidence rate ratios (IRRs) were 1.28 (95% CI, 1.06-1.55) for moderate exacerbations and 1.55 (1.20-2.00) for severe exacerbations for individuals with blood eosinophil counts >0.29 × 109/L (highest tertile) vs individuals with blood eosinophil counts <0.18 × 109/L (lowest tertile). For blood neutrophils, the multivariable-adjusted IRRs were 2.14 (1.74-2.63) for moderate exacerbations and 1.18 (0.89-1.55) for severe exacerbations for individuals with blood neutrophil counts >4.85 × 109/L (highest tertile) vs individuals with blood neutrophil counts <3.77 × 109/L (lowest tertile). Blood eosinophil and neutrophil counts interacted on moderate exacerbations (P = 3 × 10-4), but not on severe exacerbations. CONCLUSIONS High blood eosinophil counts are associated with an increased risk of both moderate and severe asthma exacerbations, while high blood neutrophil counts are associated with an increased risk of moderate, but not severe exacerbations.

Statin Use Is Associated with Reduced Mortality in Patients with Interstitial Lung Disease

Introduction We hypothesized that statin use begun before the diagnosis of interstitial lung disease is associated with reduced mortality. Methods We studied all patients diagnosed with interstitial lung disease in the entire Danish population from 1995 through 2009, comparing statin use versus no statin use in a nested 1:2 matched study. Results The cumulative survival as a function of follow-up time from the date of diagnosis of interstitial lung disease (n = 1,786+3,572) and idiopathic lung fibrosis (n = 261+522) was higher for statin users versus never users (log-rank: P = 7·10−9 and P = 0.05). The median survival time in patients with interstitial lung disease was 3.3 years in statin users and 2.1 years in never users. Corresponding values in patients with idiopathic lung fibrosis were 3.4 versus 2.4 years. After multivariable adjustment, the hazard ratio for all-cause mortality for statin users versus never users was 0.73 (95% confidence interval, 0.68 to 0.79) in patients with interstitial lung disease and 0.76 (0.62 to 0.93) in patients with idiopathic lung fibrosis. Results were robust in all sensitivity analyses. Conclusion Among patients with interstitial lung disease statin use was associated with reduced all-cause mortality.

Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis

Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures Coronary heart disease. Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10−37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10−12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

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.

Plasma urate, lung function and chronic obstructive pulmonary disease: a Mendelian randomisation study in 114 979 individuals from the general population

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.

AHRR hypomethylation, lung function, lung function decline, and respiratory symptoms

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 (FEV1) after multivariable adjustment including smoking. Hypomethylation was also associated with a lower z-score for both forced vital capacity (FVC) and FEV1/FVC. In prospective analyses, individuals in the lowest versus highest tertile of methylation extent had a steeper decline in FEV1/height3 (p for examination×methylation interaction=0.003) and FVC/height3 (p=0.01), but not FEV1/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. AHRR hypomethylation is associated with low lung function, steeper lung function decline, and respiratory symptoms http://ow.ly/a30J30hB2dS

Blood eosinophil count and risk of pneumonia hospitalisations in individuals with COPD

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 (FEV1) <50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded. Among individuals with COPD and FEV1 <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 ≥0.34×109 cells·L−1 versus <0.34×109 cells·L−1. In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV1 <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 FEV1 ≥50% pred. In individuals with COPD and FEV1 <50% pred, blood eosinophil count ≥0.34×109 cells·L−1 was associated with high risk of hospitalisation due to pneumonia. Eosinophilic COPD with severely impaired lung function is associated with high risk of pneumonia hospitalisations http://ow.ly/Tyl130jsi1D

TP53 Arg72Pro, mortality after cancer, and all-cause mortality in 105,200 individuals

Rs1042522 (Arg72Pro) is a functional polymorphism of TP53. Pro72 has been associated with lower all-cause mortality and lower mortality after cancer. We hypothesized that TP53 Pro72 is associated with lower mortality after cancer, lower all-cause mortality, and with increased cancer incidence in the general population in a contemporary cohort. We genotyped 105,200 individuals aged 20–100 years from the Copenhagen General Population Study, recruited in 2003–2013, and followed them in Danish health registries. During follow-up 5,531 individuals died and 5,849 developed cancer. Hazard ratios for mortality after cancer were 1.03 (95% confidence interval:0.93–1.15) for Arg/Pro and 0.96 (95% CI:0.79–1.18) for Pro/Pro versus Arg/Arg. Hazard ratios for all-cause mortality were 0.99 (95% CI:0.93–1.04) for Arg/Pro and 1.09 (95% CI:0.98–1.21) for Pro/Pro versus Arg/Arg. Risk of cancer specific mortality, cardiovascular mortality, and respiratory mortality were not associated with Arg72Pro genotype overall; however, in exploratory subgroup analyses, genotype-associated risks of malignant melanoma and diabetes were altered. Considering multiple comparisons the latter findings may represent play of chance. The TP53 Arg72Pro genotype was not associated with mortality after cancer, all-cause mortality, or cancer incidence in the general population in a contemporary cohort. Our main conclusion is therefore a lack of reproducing an effect of TP53 Arg72Pro genotype on mortality.

Morbidity and Mortality in 7,684 Women According to Personal Hair Dye Use: The Copenhagen City Heart Study followed for 37 Years

Background Permanent hair dye contains aromatic amines which are carcinogenic, and can cause allergic skin reactions. In the long term personal use of hair dye might therefore influence both morbidity and mortality. Objectives We tested the hypothesis that personal use of hair dye in women is associated with increased morbidity and mortality in the general population. Methods We included 7,684 women from the Copenhagen City Heart Study with information on the use of personal hair dye. We assessed the risk of cancer, skin diseases, other morbidities, and mortality during a median follow-up of 27 years (range 0–37). Results The multivariable adjusted hazard ratio for malignant melanoma in women with versus without personal use of hair dye was 2.07 (95% confidence interval 1.25–3.42). There was no increased risk of other cancer types. For other skin diseases and other major causes of morbidity we found no differences between the two groups, except for a minor excess of digestive diseases and increased risk of Parkinson’s disease among women using hair dye. Finally, we found no difference in all-cause mortality comparing women using personal hair dye or not. After correction for multiple comparisons, none of the results remained significant. However, in sensitivity analysis the excess risk of malignant melanoma remained increased with a hazard ratio of 2.58 (95%CI 1.33–5.03) among users of personal hair dye. Conclusions Personal use of hair dye does not have major influences on morbidity and mortality. Our finding of a 2-fold risk of malignant melanoma in women using hair dye is hypothesis generating.