Morten Dahl - Academia.edu (original) (raw)
Papers by Morten Dahl
Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation,... more Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP). To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD. We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study. We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV(1)% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0-2.0) and 2.2 (1.2-3.9) in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L. After close matching for FEV(1)% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV(1)% predicted of less than 50. CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction.
Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation,... more Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP). To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD. We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study. We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV(1)% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0-2.0) and 2.2 (1.2-3.9) in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L. After close matching for FEV(1)% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV(1)% predicted of less than 50. CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction.
American journal of respiratory and critical care medicine, 2008
Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen ... more Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen I, hyaluronan, and heparan sulfate. Inherited change in SOD3 expression or function could affect lung matrix homeostasis and influence pulmonary function. To identify novel SOD3 polymorphisms that are associated with lung function or chronic obstructive pulmonary disease (COPD). Resequencing of 182 individuals identified two novel polymorphisms, E1 (rs8192287) and I1 (rs8192288), in a conserved region of the SOD3 gene of potential relationship to lung function. We next genotyped 9,093 individuals from the Copenhagen City Heart Study for the polymorphisms and recorded spirometry, and admissions and deaths due to COPD during 26-year follow-up. Finally, we validated our findings in a cross-sectional analysis of 35,635 individuals from the Copenhagen General Population Study. Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarrier...
Circulation, Jan 11, 2003
Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we t... more Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we tested whether alpha(1)-antitrypsin deficiency is associated with reduced blood pressure, risk of ischemic cerebrovascular (ICVD) and ischemic heart disease (IHD), and longevity. We genotyped 7963 control subjects from the adult general population of Denmark, 1131 Danish patients with ICVD, and 2221 Danish patients with IHD. Compared with MM/MS individuals, systolic blood pressure was lower by 15 mm Hg in ZZ homozygotes (n=6, P=0.03) and 9 mm Hg in MZ heterozygotes with IHD (n=39, P=0.02). Odds ratios for ICVD and IHD in MZ versus MM/MS individuals were 0.70 (0.51 to 0.96) and 0.77 (0.61 to 0.98). Finally, mean ages of MZ and MM/MS control subjects were 58 and 56 years (Mann-Whitney: P=0.008), and relative alpha(1)-antitrypsin MZ genotype frequencies increased from 20 to 93 years among control subjects (chi(2), P=0.002). ZZ alpha(1)-antitrypsin deficiency and MZ intermediate deficiency in...
The Journal of experimental medicine, Jan 17, 2004
Reduced levels of wild-type mannose-binding lectin (MBL) may increase susceptibility for infectio... more Reduced levels of wild-type mannose-binding lectin (MBL) may increase susceptibility for infection, other common diseases, and death. We investigated associations between MBL deficiency and risk of infection, other common diseases, and death during 24, 24, and 8 yr of follow-up, respectively. We genotyped 9,245 individuals from the adult Danish population for three MBL deficiency alleles, B, C, and D, as opposed to the normal noncarrier A allele. Hospitalization incidence per 10,000 person. yr was 644 in noncarriers compared with 631 in heterozygotes (log-rank: P = 0.39) and 658 in deficiency homozygotes (P = 0.53). Death incidence per 10,000 person. yr was 235 in noncarriers compared with 244 in heterozygotes (P = 0.44) and 274 in deficiency homozygotes (P = 0.12). After stratification by specific cause of hospitalization or death, only hospitalization from cardiovascular disorders was increased in deficiency homozygotes versus noncarriers (P = 0.02). When retested in two case cont...
Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmona... more Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight 2 ). Objectives: We explored distribution of low FFMI and its association with prognosisin apopulation-based cohort ofpatients
Genomics, 1998
tance regulator, which is a cyclic AMP-regulated chlo-Cystic fibrosis is the most common fatal au... more tance regulator, which is a cyclic AMP-regulated chlo-Cystic fibrosis is the most common fatal autosomal ride channel located predominantly in the apical memrecessive disease affecting Caucasian populations. It brane of epithelial cells . The most remains a puzzle how this disease is maintained at life-threatening clinical features of homozygotes or such a remarkably high incidence, however, it could compound heterozygotes caused by such mutations are be due to a reproductive advantage in cystic fibrosis pulmonary obstruction and infection, while other charheterozygotes. We tested this hypothesis. An adult Danacteristics of cystic fibrosis include pancreatic exocrine ish general population sample of 9141 individuals was insufficiency, abnormally high levels of sodium and screened for cystic fibrosis DF508 heterozygotes; 250 chloride in sweat, cirrhosis of the liver, diabetes mellicarriers of this mutation were identified (2.7%). In the tus, and infertility, especially in males (Welsh et al., total sample DF508 heterozygotes did not have more 1995). Despite such severe conditions in cystic fibrosis children than noncarriers; however, smoking interpatients, mutations causing this disease have reacted with genotype in predicting number of children mained common in Caucasian populations. This could (ANOVA: P õ 0.001). Among nonsmokers, heterozygotes had more children than noncarriers (Wilcoxon: P Å be due to a selective advantage in cystic fibrosis hetero-0.03). Among smokers, the opposite was found: heterozygotes compared with noncarriers either because hetzygotes had fewer children than noncarriers (Wilerozygotes compared with noncarriers have more chilcoxon: P Å 0.001). These findings remained significant dren (reproductive advantage) or because they resist after allowing for gender and the potential confoundother diseases better. The classic, and still the only ers of age, income, and education. Finally, after well-understood, example of such compensation is proallowing for these covariates, number of children in vided by the gene encoding sickle-cell anemia; the ho-DF508 heterozygotes decreased with increasing extent mozygous carriers of this gene die or fail to reproduce of smoking (trend test: P Å 0.003), while the opposite because of anemia, but the much more numerous hetwas true for noncarriers (trend test: P õ 0.001). In conerozygous carriers resist malaria better than normal clusion, overall these results do not support a reproindividuals (Rotter and Diamond, 1987). ductive advantage for cystic fibrosis DF508 heterozy-In the Danish population approximately 1 in 34 indigotes. However, the data cannot totally exclude the possibility that nonsmoking DF508 heterozygotes ex-viduals (2.9%) is heterozygous for a mutation causing perience a reproductive advantage while smoking cystic fibrosis, and 88% of these mutations (2.6%) are DF508 heterozygotes experience the opposite, a reprodue to a 3-bp deletion causing the loss of phenylalanine ductive disadvantage. Accordingly, the data suggest a 508 (DF508) . The high frequency previously undocumented role of smoking on fecundity of this mutation allowed us to test the hypothesis that among cystic fibrosis heterozygotes. ᭧ 1998 Academic Press cystic fibrosis DF508 heterozygotes in the general population have more children than noncarriers, using data from an adult Danish, general population sample, the
Am J Respir Crit Care Med, 2006
Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmona... more Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight 2 ). Objectives: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD. Methods: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account. Main Results: The mean FFMI was 16.0 kg/m 2 for women and 18.7 kg/m 2 for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI. Conclusions: FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD.
COPD, 2009
COPD is a complex disease with multiple pathological components, which we unfortunately tend to i... more COPD is a complex disease with multiple pathological components, which we unfortunately tend to ignore when spirometry is used as the only method to evaluate the disorder. Additional measures are needed to allow a more complete and clinically relevant assessment of COPD. The earliest potential risk factors of disease in COPD are variations in the genetic background. Genetic variations are present from conception and can determine lifelong changes in enzyme activities and protein concentrations. In contrast, measurements in blood, sputum, exhaled breath, broncho-alveolar lavage, and lung biopsies may vary substantially over time. This review explores potential markers of early disease and prognosis in COPD by examining genetic markers in the alpha(1)-antitrypsin, cystic fibrosis transmembrane conductance regulator (CFTR), and MBL-2 genes, and by examining the biochemical markers fibrinogen and C-reactive protein (CRP), which correlate with degree of pulmonary inflammation during stable conditions of COPD. Chronic lung inflammation appears to contribute to the pathogenesis of COPD, and markers of this process have promising predictive value in COPD. To implement markers for COPD in clinical practice, besides those already established for the alpha(1)-antitrypsin gene, further research and validation studies are needed.
Stroke, 2010
The development of stroke has been linked to lowered levels of epoxyeicosatrienoic acids in the c... more The development of stroke has been linked to lowered levels of epoxyeicosatrienoic acids in the cerebral microvasculature. These substances are metabolized by the enzyme-soluble epoxide hydrolase encoded by the EPHX2 gene. We tested whether genetically reduced soluble epoxide hydrolase activity is associated with risk of ischemic stroke, myocardial infarction, and ischemic heart disease. We genotyped participants from the Copenhagen City Heart Study (n=10 352), the Copenhagen General Population Study (n=26 042), the Copenhagen Carotid Stroke Study (n=398 cases+796 control subjects), and the Copenhagen Ischemic Heart Disease Study (n=4901 cases+9798 control subjects) for the R103C, R287Q, and Arg(402-403ins) variants in the EPHX2 gene and recorded hospital admissions due to ischemic stroke, myocardial infarction, and ischemic heart disease. The hazard/odds ratio for ischemic stroke did not differ from 1.0 for any of the EPHX2 genotypes or genotype combinations in the Copenhagen City Heart Study (P for trend=0.15 to 0.76), in the Copenhagen General Population Study (P for trend=0.75 to 0.95), and the Copenhagen Carotid Stroke Study (P for trend=0.08 to 1.00). Similar results were obtained for myocardial infarction and ischemic heart disease in the 3 studies. Our results show with significant power that genetically reduced soluble epoxide hydrolase activity is not a major risk factor for ischemic stroke, myocardial infarction, or ischemic heart disease in the Danish population. This suggests that the relationship between the EPHX2 gene and risk of ischemic stroke and other cardiovascular disease does not exist or its effect size is likely to be quite small.
Respiratory Medicine, 2010
Dominant mutations in the surfactant protein-C(SFTPC) gene have been linked with interstitial lun... more Dominant mutations in the surfactant protein-C(SFTPC) gene have been linked with interstitial lung disease. The frequency of lung disease due to SFTPC mutations in the general population is unknown. The aim of this study was to identify novel SFTPC mutations that are associated with lung function or disease in the general population. We resequenced the SFTPC gene in 760 individuals and identified 18 genetic variants, of which 5 were novel. Of the five novel mutations, two were situated in highly conserved areas of the SFTPC gene: A53T and Y106X. We genotyped the Copenhagen City Heart Study(n=10,604) and the Copenhagen General Population Study(n=37,337) to assess the clinical relevance of these mutations. Genotyping identified 36 individuals heterozygous for A53T and 3 individuals heterozygous for Y106X. A53T heterozygotes and Y106X heterozygotes did not differ from non-carriers in FEV(1)% predicted, FVC% predicted or FEV(1)/FVC. A53T heterozygotes had a two-fold increased risk for asthma in the Copenhagen City Heart Study and Copenhagen General Population Study combined (adjusted odds ratio 2.2(1.0-4.9)). A53T heterozygotes did not differ consistently from non-carriers in risk of chronic obstructive pulmonary disease or interstitial lung disease. No Y106X heterozygotes suffered from asthma, chronic obstructive pulmonary disease (COPD), or interstitial lung disease. We identified two novel mutations in highly conserved areas of the SFTPC gene, and show that heterozygotes for the mutations have normal lung function and are unaffected by COPD and interstitial lung disease. A53T heterozygotes had increased asthma risk, but further research is required to conclusively determine whether this mutation is associated with asthma.
A23. IDIOPATHIC PULMONARY FIBROSIS: EPIDEMIOLOGY, BIOMARKERS, AND OUTCOMES, 2010
Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We e... more Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We examined the association between ever-diagnosed venous thromboembolism and risk of incident idiopathic interstitial pneumonia. Venous thromboembolism was taken as a proxy for a procoagulant state in an individual. We conducted a study of the entire Danish population from 1980 through 2007, comprising 7.4 million individuals. Incident idiopathic interstitial pneumonia, ever-diagnosed venous thromboembolism, and use of prescription anticoagulants were drawn from national Danish registries. Age-standardized incidence rates per 10,000 person-years for idiopathic interstitial pneumonia were higher among those ever diagnosed with venous thromboembolism (1.8; n = 158,676), pulmonary embolism (2.8; n = 70,586), and deep venous thrombosis only (1.2; n = 88,090), than among control subjects (0.8; n = 7,260,278). Multivariate-adjusted hazard ratios for idiopathic interstitial pneumonia were 1.8 (95% confidence interval [CI], 1.7-1.9) in those ever diagnosed with venous thromboembolism, 2.4 (95% CI, 2.3-2.6) in those ever diagnosed with pulmonary embolism, and 1.3 (95% CI, 1.2-1.4) in those ever diagnosed with deep venous thrombosis only, compared with control subjects. Corresponding hazard ratios in those ever diagnosed with venous thromboembolism stratified in those ever and never treated with anticoagulants were 1.4 (95% CI, 1.2-1.6) and 2.8 (95% CI, 2.4-3.1) (venous thromboembolism x anticoagulation use interaction on idiopathic interstitial pneumonia outcome: P = 1.5 x 10(-10)). In the general population, ever-diagnosed venous thromboembolism was associated with idiopathic interstitial pneumonia, particularly among those never treated with anticoagulants.
Am J Respir Crit Care Med, 2010
Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We e... more Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We examined the association between ever-diagnosed venous thromboembolism and risk of incident idiopathic interstitial pneumonia. Venous thromboembolism was taken as a proxy for a procoagulant state in an individual. We conducted a study of the entire Danish population from 1980 through 2007, comprising 7.4 million individuals. Incident idiopathic interstitial pneumonia, ever-diagnosed venous thromboembolism, and use of prescription anticoagulants were drawn from national Danish registries. Age-standardized incidence rates per 10,000 person-years for idiopathic interstitial pneumonia were higher among those ever diagnosed with venous thromboembolism (1.8; n = 158,676), pulmonary embolism (2.8; n = 70,586), and deep venous thrombosis only (1.2; n = 88,090), than among control subjects (0.8; n = 7,260,278). Multivariate-adjusted hazard ratios for idiopathic interstitial pneumonia were 1.8 (95% confidence interval [CI], 1.7-1.9) in those ever diagnosed with venous thromboembolism, 2.4 (95% CI, 2.3-2.6) in those ever diagnosed with pulmonary embolism, and 1.3 (95% CI, 1.2-1.4) in those ever diagnosed with deep venous thrombosis only, compared with control subjects. Corresponding hazard ratios in those ever diagnosed with venous thromboembolism stratified in those ever and never treated with anticoagulants were 1.4 (95% CI, 1.2-1.6) and 2.8 (95% CI, 2.4-3.1) (venous thromboembolism x anticoagulation use interaction on idiopathic interstitial pneumonia outcome: P = 1.5 x 10(-10)). In the general population, ever-diagnosed venous thromboembolism was associated with idiopathic interstitial pneumonia, particularly among those never treated with anticoagulants.
B38. CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATHOGENESIS II, 2010
European Respiratory Journal, 2011
We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal e... more We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal epoxide hydrolase gene (EPHX1), T113C and A139G, may influence susceptibility to chronic obstructive pulmonary disease (COPD) and asthma. We genotyped participants from the Copenhagen City Heart Study (n = 10,038) and the Copenhagen General Population Study (n = 37,022) for the T113C and A139G variants in the EPHX1 gene and measured lung function and recorded COPD hospitalisation and asthma and smoking history. Finally, we meta-analysed results from 19 studies including 7,489 COPD cases and 42,970 controls. The OR for spirometry-defined COPD or COPD hospitalisation did not differ from 1.0 for any of the EPHX1 genotypes or phenotypes overall, or in smokers or nonsmokers separately (p-value for trend 0.18-0.91). Likewise, EPHX1 genotypes or phenotypes did not associate with risk of asthma (p-value for trend 0.46-0.98). In meta-analysis, random effects OR for COPD in T113C heterozygotes and homozygotes versus non-carriers were 1.17 (0.99-1.38) and 1.38 (1.09-1.74), respectively. Corresponding values for A139G were 0.93 (0.83-1.05) and 0.89 (0.78-1.02). Our results indicate that genetically reduced microsomal epoxide hydrolase activity is not a major risk factor for COPD or asthma in the Danish population; however, meta-analysis cannot completely exclude a minor effect on COPD risk.
A50. COPD EPIDEMIOLOGY, 2011
C51. ASTHMA EPIDEMIOLOGY, 2011
A33. GENETIC AND EPIGENETIC REGULATION OF LUNG DISEASE, 2011
B41. COPD AND ASSOCIATED COMORBIDITIES, 2011
C22. PATHOBIOLOGY OF COPD: LESSONS FROM INFLAMMATORY MECHANISMS AND GENOMIC STUDIES, 2011
Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation,... more Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP). To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD. We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study. We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV(1)% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0-2.0) and 2.2 (1.2-3.9) in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L. After close matching for FEV(1)% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV(1)% predicted of less than 50. CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction.
Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation,... more Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP). To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD. We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study. We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV(1)% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0-2.0) and 2.2 (1.2-3.9) in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L. After close matching for FEV(1)% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV(1)% predicted of less than 50. CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction.
American journal of respiratory and critical care medicine, 2008
Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen ... more Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen I, hyaluronan, and heparan sulfate. Inherited change in SOD3 expression or function could affect lung matrix homeostasis and influence pulmonary function. To identify novel SOD3 polymorphisms that are associated with lung function or chronic obstructive pulmonary disease (COPD). Resequencing of 182 individuals identified two novel polymorphisms, E1 (rs8192287) and I1 (rs8192288), in a conserved region of the SOD3 gene of potential relationship to lung function. We next genotyped 9,093 individuals from the Copenhagen City Heart Study for the polymorphisms and recorded spirometry, and admissions and deaths due to COPD during 26-year follow-up. Finally, we validated our findings in a cross-sectional analysis of 35,635 individuals from the Copenhagen General Population Study. Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarrier...
Circulation, Jan 11, 2003
Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we t... more Because elastase in alpha(1)-antitrypsin deficiency may attack elastin in the arterial wall, we tested whether alpha(1)-antitrypsin deficiency is associated with reduced blood pressure, risk of ischemic cerebrovascular (ICVD) and ischemic heart disease (IHD), and longevity. We genotyped 7963 control subjects from the adult general population of Denmark, 1131 Danish patients with ICVD, and 2221 Danish patients with IHD. Compared with MM/MS individuals, systolic blood pressure was lower by 15 mm Hg in ZZ homozygotes (n=6, P=0.03) and 9 mm Hg in MZ heterozygotes with IHD (n=39, P=0.02). Odds ratios for ICVD and IHD in MZ versus MM/MS individuals were 0.70 (0.51 to 0.96) and 0.77 (0.61 to 0.98). Finally, mean ages of MZ and MM/MS control subjects were 58 and 56 years (Mann-Whitney: P=0.008), and relative alpha(1)-antitrypsin MZ genotype frequencies increased from 20 to 93 years among control subjects (chi(2), P=0.002). ZZ alpha(1)-antitrypsin deficiency and MZ intermediate deficiency in...
The Journal of experimental medicine, Jan 17, 2004
Reduced levels of wild-type mannose-binding lectin (MBL) may increase susceptibility for infectio... more Reduced levels of wild-type mannose-binding lectin (MBL) may increase susceptibility for infection, other common diseases, and death. We investigated associations between MBL deficiency and risk of infection, other common diseases, and death during 24, 24, and 8 yr of follow-up, respectively. We genotyped 9,245 individuals from the adult Danish population for three MBL deficiency alleles, B, C, and D, as opposed to the normal noncarrier A allele. Hospitalization incidence per 10,000 person. yr was 644 in noncarriers compared with 631 in heterozygotes (log-rank: P = 0.39) and 658 in deficiency homozygotes (P = 0.53). Death incidence per 10,000 person. yr was 235 in noncarriers compared with 244 in heterozygotes (P = 0.44) and 274 in deficiency homozygotes (P = 0.12). After stratification by specific cause of hospitalization or death, only hospitalization from cardiovascular disorders was increased in deficiency homozygotes versus noncarriers (P = 0.02). When retested in two case cont...
Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmona... more Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight 2 ). Objectives: We explored distribution of low FFMI and its association with prognosisin apopulation-based cohort ofpatients
Genomics, 1998
tance regulator, which is a cyclic AMP-regulated chlo-Cystic fibrosis is the most common fatal au... more tance regulator, which is a cyclic AMP-regulated chlo-Cystic fibrosis is the most common fatal autosomal ride channel located predominantly in the apical memrecessive disease affecting Caucasian populations. It brane of epithelial cells . The most remains a puzzle how this disease is maintained at life-threatening clinical features of homozygotes or such a remarkably high incidence, however, it could compound heterozygotes caused by such mutations are be due to a reproductive advantage in cystic fibrosis pulmonary obstruction and infection, while other charheterozygotes. We tested this hypothesis. An adult Danacteristics of cystic fibrosis include pancreatic exocrine ish general population sample of 9141 individuals was insufficiency, abnormally high levels of sodium and screened for cystic fibrosis DF508 heterozygotes; 250 chloride in sweat, cirrhosis of the liver, diabetes mellicarriers of this mutation were identified (2.7%). In the tus, and infertility, especially in males (Welsh et al., total sample DF508 heterozygotes did not have more 1995). Despite such severe conditions in cystic fibrosis children than noncarriers; however, smoking interpatients, mutations causing this disease have reacted with genotype in predicting number of children mained common in Caucasian populations. This could (ANOVA: P õ 0.001). Among nonsmokers, heterozygotes had more children than noncarriers (Wilcoxon: P Å be due to a selective advantage in cystic fibrosis hetero-0.03). Among smokers, the opposite was found: heterozygotes compared with noncarriers either because hetzygotes had fewer children than noncarriers (Wilerozygotes compared with noncarriers have more chilcoxon: P Å 0.001). These findings remained significant dren (reproductive advantage) or because they resist after allowing for gender and the potential confoundother diseases better. The classic, and still the only ers of age, income, and education. Finally, after well-understood, example of such compensation is proallowing for these covariates, number of children in vided by the gene encoding sickle-cell anemia; the ho-DF508 heterozygotes decreased with increasing extent mozygous carriers of this gene die or fail to reproduce of smoking (trend test: P Å 0.003), while the opposite because of anemia, but the much more numerous hetwas true for noncarriers (trend test: P õ 0.001). In conerozygous carriers resist malaria better than normal clusion, overall these results do not support a reproindividuals (Rotter and Diamond, 1987). ductive advantage for cystic fibrosis DF508 heterozy-In the Danish population approximately 1 in 34 indigotes. However, the data cannot totally exclude the possibility that nonsmoking DF508 heterozygotes ex-viduals (2.9%) is heterozygous for a mutation causing perience a reproductive advantage while smoking cystic fibrosis, and 88% of these mutations (2.6%) are DF508 heterozygotes experience the opposite, a reprodue to a 3-bp deletion causing the loss of phenylalanine ductive disadvantage. Accordingly, the data suggest a 508 (DF508) . The high frequency previously undocumented role of smoking on fecundity of this mutation allowed us to test the hypothesis that among cystic fibrosis heterozygotes. ᭧ 1998 Academic Press cystic fibrosis DF508 heterozygotes in the general population have more children than noncarriers, using data from an adult Danish, general population sample, the
Am J Respir Crit Care Med, 2006
Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmona... more Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight 2 ). Objectives: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD. Methods: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account. Main Results: The mean FFMI was 16.0 kg/m 2 for women and 18.7 kg/m 2 for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI. Conclusions: FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD.
COPD, 2009
COPD is a complex disease with multiple pathological components, which we unfortunately tend to i... more COPD is a complex disease with multiple pathological components, which we unfortunately tend to ignore when spirometry is used as the only method to evaluate the disorder. Additional measures are needed to allow a more complete and clinically relevant assessment of COPD. The earliest potential risk factors of disease in COPD are variations in the genetic background. Genetic variations are present from conception and can determine lifelong changes in enzyme activities and protein concentrations. In contrast, measurements in blood, sputum, exhaled breath, broncho-alveolar lavage, and lung biopsies may vary substantially over time. This review explores potential markers of early disease and prognosis in COPD by examining genetic markers in the alpha(1)-antitrypsin, cystic fibrosis transmembrane conductance regulator (CFTR), and MBL-2 genes, and by examining the biochemical markers fibrinogen and C-reactive protein (CRP), which correlate with degree of pulmonary inflammation during stable conditions of COPD. Chronic lung inflammation appears to contribute to the pathogenesis of COPD, and markers of this process have promising predictive value in COPD. To implement markers for COPD in clinical practice, besides those already established for the alpha(1)-antitrypsin gene, further research and validation studies are needed.
Stroke, 2010
The development of stroke has been linked to lowered levels of epoxyeicosatrienoic acids in the c... more The development of stroke has been linked to lowered levels of epoxyeicosatrienoic acids in the cerebral microvasculature. These substances are metabolized by the enzyme-soluble epoxide hydrolase encoded by the EPHX2 gene. We tested whether genetically reduced soluble epoxide hydrolase activity is associated with risk of ischemic stroke, myocardial infarction, and ischemic heart disease. We genotyped participants from the Copenhagen City Heart Study (n=10 352), the Copenhagen General Population Study (n=26 042), the Copenhagen Carotid Stroke Study (n=398 cases+796 control subjects), and the Copenhagen Ischemic Heart Disease Study (n=4901 cases+9798 control subjects) for the R103C, R287Q, and Arg(402-403ins) variants in the EPHX2 gene and recorded hospital admissions due to ischemic stroke, myocardial infarction, and ischemic heart disease. The hazard/odds ratio for ischemic stroke did not differ from 1.0 for any of the EPHX2 genotypes or genotype combinations in the Copenhagen City Heart Study (P for trend=0.15 to 0.76), in the Copenhagen General Population Study (P for trend=0.75 to 0.95), and the Copenhagen Carotid Stroke Study (P for trend=0.08 to 1.00). Similar results were obtained for myocardial infarction and ischemic heart disease in the 3 studies. Our results show with significant power that genetically reduced soluble epoxide hydrolase activity is not a major risk factor for ischemic stroke, myocardial infarction, or ischemic heart disease in the Danish population. This suggests that the relationship between the EPHX2 gene and risk of ischemic stroke and other cardiovascular disease does not exist or its effect size is likely to be quite small.
Respiratory Medicine, 2010
Dominant mutations in the surfactant protein-C(SFTPC) gene have been linked with interstitial lun... more Dominant mutations in the surfactant protein-C(SFTPC) gene have been linked with interstitial lung disease. The frequency of lung disease due to SFTPC mutations in the general population is unknown. The aim of this study was to identify novel SFTPC mutations that are associated with lung function or disease in the general population. We resequenced the SFTPC gene in 760 individuals and identified 18 genetic variants, of which 5 were novel. Of the five novel mutations, two were situated in highly conserved areas of the SFTPC gene: A53T and Y106X. We genotyped the Copenhagen City Heart Study(n=10,604) and the Copenhagen General Population Study(n=37,337) to assess the clinical relevance of these mutations. Genotyping identified 36 individuals heterozygous for A53T and 3 individuals heterozygous for Y106X. A53T heterozygotes and Y106X heterozygotes did not differ from non-carriers in FEV(1)% predicted, FVC% predicted or FEV(1)/FVC. A53T heterozygotes had a two-fold increased risk for asthma in the Copenhagen City Heart Study and Copenhagen General Population Study combined (adjusted odds ratio 2.2(1.0-4.9)). A53T heterozygotes did not differ consistently from non-carriers in risk of chronic obstructive pulmonary disease or interstitial lung disease. No Y106X heterozygotes suffered from asthma, chronic obstructive pulmonary disease (COPD), or interstitial lung disease. We identified two novel mutations in highly conserved areas of the SFTPC gene, and show that heterozygotes for the mutations have normal lung function and are unaffected by COPD and interstitial lung disease. A53T heterozygotes had increased asthma risk, but further research is required to conclusively determine whether this mutation is associated with asthma.
A23. IDIOPATHIC PULMONARY FIBROSIS: EPIDEMIOLOGY, BIOMARKERS, AND OUTCOMES, 2010
Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We e... more Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We examined the association between ever-diagnosed venous thromboembolism and risk of incident idiopathic interstitial pneumonia. Venous thromboembolism was taken as a proxy for a procoagulant state in an individual. We conducted a study of the entire Danish population from 1980 through 2007, comprising 7.4 million individuals. Incident idiopathic interstitial pneumonia, ever-diagnosed venous thromboembolism, and use of prescription anticoagulants were drawn from national Danish registries. Age-standardized incidence rates per 10,000 person-years for idiopathic interstitial pneumonia were higher among those ever diagnosed with venous thromboembolism (1.8; n = 158,676), pulmonary embolism (2.8; n = 70,586), and deep venous thrombosis only (1.2; n = 88,090), than among control subjects (0.8; n = 7,260,278). Multivariate-adjusted hazard ratios for idiopathic interstitial pneumonia were 1.8 (95% confidence interval [CI], 1.7-1.9) in those ever diagnosed with venous thromboembolism, 2.4 (95% CI, 2.3-2.6) in those ever diagnosed with pulmonary embolism, and 1.3 (95% CI, 1.2-1.4) in those ever diagnosed with deep venous thrombosis only, compared with control subjects. Corresponding hazard ratios in those ever diagnosed with venous thromboembolism stratified in those ever and never treated with anticoagulants were 1.4 (95% CI, 1.2-1.6) and 2.8 (95% CI, 2.4-3.1) (venous thromboembolism x anticoagulation use interaction on idiopathic interstitial pneumonia outcome: P = 1.5 x 10(-10)). In the general population, ever-diagnosed venous thromboembolism was associated with idiopathic interstitial pneumonia, particularly among those never treated with anticoagulants.
Am J Respir Crit Care Med, 2010
Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We e... more Idiopathic interstitial pneumonia is characterized by pulmonary fibrosis and high mortality. We examined the association between ever-diagnosed venous thromboembolism and risk of incident idiopathic interstitial pneumonia. Venous thromboembolism was taken as a proxy for a procoagulant state in an individual. We conducted a study of the entire Danish population from 1980 through 2007, comprising 7.4 million individuals. Incident idiopathic interstitial pneumonia, ever-diagnosed venous thromboembolism, and use of prescription anticoagulants were drawn from national Danish registries. Age-standardized incidence rates per 10,000 person-years for idiopathic interstitial pneumonia were higher among those ever diagnosed with venous thromboembolism (1.8; n = 158,676), pulmonary embolism (2.8; n = 70,586), and deep venous thrombosis only (1.2; n = 88,090), than among control subjects (0.8; n = 7,260,278). Multivariate-adjusted hazard ratios for idiopathic interstitial pneumonia were 1.8 (95% confidence interval [CI], 1.7-1.9) in those ever diagnosed with venous thromboembolism, 2.4 (95% CI, 2.3-2.6) in those ever diagnosed with pulmonary embolism, and 1.3 (95% CI, 1.2-1.4) in those ever diagnosed with deep venous thrombosis only, compared with control subjects. Corresponding hazard ratios in those ever diagnosed with venous thromboembolism stratified in those ever and never treated with anticoagulants were 1.4 (95% CI, 1.2-1.6) and 2.8 (95% CI, 2.4-3.1) (venous thromboembolism x anticoagulation use interaction on idiopathic interstitial pneumonia outcome: P = 1.5 x 10(-10)). In the general population, ever-diagnosed venous thromboembolism was associated with idiopathic interstitial pneumonia, particularly among those never treated with anticoagulants.
B38. CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATHOGENESIS II, 2010
European Respiratory Journal, 2011
We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal e... more We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal epoxide hydrolase gene (EPHX1), T113C and A139G, may influence susceptibility to chronic obstructive pulmonary disease (COPD) and asthma. We genotyped participants from the Copenhagen City Heart Study (n = 10,038) and the Copenhagen General Population Study (n = 37,022) for the T113C and A139G variants in the EPHX1 gene and measured lung function and recorded COPD hospitalisation and asthma and smoking history. Finally, we meta-analysed results from 19 studies including 7,489 COPD cases and 42,970 controls. The OR for spirometry-defined COPD or COPD hospitalisation did not differ from 1.0 for any of the EPHX1 genotypes or phenotypes overall, or in smokers or nonsmokers separately (p-value for trend 0.18-0.91). Likewise, EPHX1 genotypes or phenotypes did not associate with risk of asthma (p-value for trend 0.46-0.98). In meta-analysis, random effects OR for COPD in T113C heterozygotes and homozygotes versus non-carriers were 1.17 (0.99-1.38) and 1.38 (1.09-1.74), respectively. Corresponding values for A139G were 0.93 (0.83-1.05) and 0.89 (0.78-1.02). Our results indicate that genetically reduced microsomal epoxide hydrolase activity is not a major risk factor for COPD or asthma in the Danish population; however, meta-analysis cannot completely exclude a minor effect on COPD risk.
A50. COPD EPIDEMIOLOGY, 2011
C51. ASTHMA EPIDEMIOLOGY, 2011
A33. GENETIC AND EPIGENETIC REGULATION OF LUNG DISEASE, 2011
B41. COPD AND ASSOCIATED COMORBIDITIES, 2011
C22. PATHOBIOLOGY OF COPD: LESSONS FROM INFLAMMATORY MECHANISMS AND GENOMIC STUDIES, 2011