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Background and aims: High levels of lipoprotein(a) could worsen the outcome of COVID-19 due to prothrombotic and proinflammatory properties of lipoprotein(a). We tested the hypotheses that during COVID-19 hospitalization i) increased thrombotic activity and inflammation are associated with lipoprotein(a) levels, and ii) lipoprotein(a) levels are associated with rate of hospital death and discharge. Methods: We studied 211 patients admitted to Copenhagen University Hospital in 2020 with COVID-19, that is, prior to any vaccination. Thrombotic activity was marked by elevated D-dimer while inflammation was marked by elevated interleukin-6, C-reactive protein, and procalcitonin. Patients were followed until death (N = 36) or discharge (N = 175). Results: A 2-fold higher D-dimer was associated with 14% (95%CI: 8.1–20%) higher lipoprotein(a). Conversely, 2-fold higher interleukin-6, C-reactive protein, and procalcitonin were associated with respectively 4.3% (0.62–7.8%), 5.7% (0.15–5.2%), and 8.7% (5.2–12%) lower lipoprotein(a). For hospital death, the multivariable adjusted hazard ratio per 2-fold higher lipoprotein(a) was 1.26 (95%CI:0.91–1.73). Corresponding hazard ratios per 2-fold higher biomarker were 0.93 (0.75–1.16) for D-dimer, 1.42 (1.17–1.73) for interleukin-6, 1.44 (0.95–2.17) for C-reactive protein, and 1.44 (1.20–1.73) for procalcitonin. For hospital discharge, the multivariable adjusted hazard ratio per 2-fold higher lipoprotein(a) was 0.91 (95%CI:0.79–1.06). Corresponding hazard ratios per 2-fold higher biomarker were 0.86 (0.75–0.98) for D-dimer, 0.84 (0.76–0.92) for interleukin-6, 0.80 (0.71–0.90) for C-reactive protein, and 0.76 (0.67–0.88) for procalcitonin. Conclusions: In COVID-19 patients, thrombotic activity marked by elevated D-dimer was associated with higher lipoprotein(a) while elevated inflammatory biomarkers of interleukin-6, C-reactive protein, and procalcitonin were associated with lower lipoprotein(a); however, elevated lipoprotein(a) was not associated with rate of hospital death or discharge.

Background: A genetic variant in the manganese transporter SLC30A10 (rs188273166, p.Thr95Ile) was associated with increased plasma alanine transaminase (ALT) in a recent genome-wide association study in the UK Biobank (UKB). The aims of the present study were to test the association of rs188273166 with ALT in an independent cohort, and to begin to assess the clinical, hepatic, and biochemical phenotypes associated with the variant. Methods: We included n = 334,886 white participants from UKB, including 14,462 with hepatic magnetic resonance imaging (MRI), and n = 113,612 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study combined. Results: Genotyping SLC30A10 p.Thr95Ile identified 816 heterozygotes in the UKB and 111 heterozygotes in the Copenhagen cohort. Compared to noncarriers, heterozygotes had 4 and 5 U/L higher levels of ALT in the UKB and Copenhagen cohort, respectively, and 3 U/L higher plasma aspartate transaminase and gamma-glutamyl transferase in the UKB. Heterozygotes also had higher corrected T1 on liver MRI, a marker of hepatic inflammation (p = 4 × 10–7), but no change in MRI-quantified steatosis (p = 0.57). Plasma manganese was within the normal range in nine heterozygotes that provided new blood samples. SLC30A10 p.Thr95Ile heterozygotes had an eightfold increased risk of biliary tract cancer in UKB (p = 4 × 10–7), but this association was not replicated in the Copenhagen cohort. Conclusions: SLC30A10 p.Thr95Ile was associated with elevated liver enzymes in two large general population cohorts, and with MRI-quantified hepatic inflammation. Graphical abstract: A rare genetic variant (p.Thr95Ile) in the manganese transporter SLC30A10 is associated with elevated plasma alanine transaminase (ALT) and higher corrected T1 on liver MRI, markers of liver inflammation. These data support that the variant may increase the risk of liver disease. [Figure not available: see fulltext.]

Background and aims: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH.Methods: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice.Results: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant.Conclusions: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening. Background and aims: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. Methods: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. Results: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. Conclusions: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

BACKGROUND: Genetically elevated plasma lipoprotein(a) and familial hypercholesterolemia each result in premature atherosclerotic cardiovascular disease (ASCVD); however, a direct comparison in the same population is needed of these 2 genetic traits on the risk of ASCVD.OBJECTIVES: We determined the level of plasma lipoprotein(a) that is equivalent to low-density lipoprotein (LDL) cholesterol in clinically and genetically diagnosed familial hypercholesterolemia on risk of myocardial infarction and ASCVD.METHODS: We examined the CGPS (Copenhagen General Population Study) with determination of lipoprotein(a) and familial hypercholesterolemia in 69,644 individuals followed for 42 years, during which time, 4,166 developed myocardial infarction and 11,464, ASCVD.RESULTS: For risk of myocardial infarction, the plasma lipoprotein(a) level equivalent to LDL cholesterol in clinical familial hypercholesterolemia was 67 mg/dL (142 nmol/L) for MEDPED (Make Early Diagnosis to Prevent Early Death), 110 mg/dL (236 nmol/L) for Simon Broome, 256 mg/dL (554 nmol/L) for possible DLCN (Dutch Lipid Clinic Network), and 402 mg/dL (873 nmol/L) for probable+definite DLCN, whereas it was 180 mg/dL (389 nmol/L) for genetic familial hypercholesterolemia. Corresponding values for ASCVD were 130 mg/dL (280 nmol/L), 150 mg/dL (323 nmol/L), 227 mg/dL (491 nmol/L), 391 mg/dL (849 nmol/L), and 175 mg/dL (378 nmol/L), respectively. Individuals with both elevated lipoprotein(a) and either familial hypercholesterolemia or a family history of premature myocardial infarction had a higher risk of myocardial infarction and ASCVD compared with individuals with only 1 of these genetic traits, with the highest HRs being for lipoprotein(a) upper 20% vs lower 50% of 14.0 (95% CI: 9.15-21.3) for myocardial infarction and 5.05 (95% CI: 3.41-7.48) for ASCVD.CONCLUSIONS: Lipoprotein(a) levels equivalent to LDL cholesterol in clinical and genetic familial hypercholesterolemia were 67 to 402 mg/dL and 180 mg/dL, respectively, for myocardial infarction and 130 to 391 mg/dL and 175 mg/dL, respectively, for ASCVD.

BACKGROUND: Whether risk of exacerbations of chronic obstructive pulmonary disease (COPD) is influenced by severity of symptoms and maintenance treatment is unclear.OBJECTIVE: We hypothesized that in addition to history of exacerbations of COPD, the severity of dyspnoea and use of maintenance medications are associated with risk of future exacerbations.METHODS: We included 96,462 adults from the Copenhagen General Population Study and assessed risk of moderate and severe exacerbations from 2003 to 2013 according to exacerbation history, dyspnoea score (mMRC), and presence/absence of maintenance treatment with inhaled long-acting bronchodilators and/or inhaled corticosteroids.FINDINGS: Among 13,380 individuals with COPD, we observed 1543 moderate and 348 severe exacerbations. In treatment naïve individuals and in those on maintenance treatment, history of previous exacerbations and to a smaller degree also dyspnoea were associated with a higher risk of future exacerbations; 32% of the treatment naïve individuals with mMRC≥2 and a single moderate exacerbation in the previous year experienced a moderate exacerbation during the following year compared with only 3% in the individuals with similar severity of dyspnoea but no exacerbations in the previous year yielding an adjusted hazard ratio of 6.26 (95% confidence interval, 3.70-10.58).INTERPRETATION: This observational study of the general population suggests that in addition to exacerbation history also the severity of dyspnoea predicts the risk of future COPD exacerbations. In subjects with severe dyspnoea, a history of a single moderate exacerbation is associated with a high risk of future exacerbations, suggesting that this subgroup needs special attention in order to prevent these events.

Increased elastase activity in αWe genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish ααIndividuals with severe α

Smoking has been associated with opposing risks of ulcerative colitis and Crohn's disease. Whether these observational associations reflect actual causal associations, confounding, or reverse causation is unclear. Using a Mendelian randomization approach, we tested the hypothesis that smoking protects against ulcerative colitis and is a cause of Crohn's disease. We included 118,683 white Danes aged ≥ 20 from the Copenhagen General Population Study (2003-2015) and the Copenhagen City Heart Study (1991-94 and 2001-03). During follow-up until 2018, we investigated the association of smoking and CHRNA3 rs1051730, where the T-allele is strongly associated with nicotine dependence, with risk of ulcerative colitis and Crohn's disease. We identified 1312 cases of ulcerative colitis and 671 cases of Crohn's disease. Compared to never-smokers, multivariable adjusted hazard ratios (HRs) for ulcerative colitis were 1.69(95% confidence interval [CI] 1.32-2.15) in former smokers and 2.27(1.74-2.96) in current smokers. Corresponding HRs for Crohn's disease were 1.31(0.93-1.84) and 1.93(1.34-2.78), respectively. Among ever-smokers when compared to non-carriers of the CHRNA3 rs1051730 T-allele, age and sex adjusted HRs for risk of ulcerative colitis were 1.03(95%CI 0.89-1.18) in heterozygotes and 0.91(0.72-1.16) in homozygotes. Corresponding HRs for Crohn's disease were 1.05(0.87-1.28) and 1.02(0.74-1.41), respectively. In a meta-analysis combined with UK Biobank, there was no evidence that CHRNA3 rs1051730 was associated with risk of ulcerative colitis or Crohn's disease. In conclusion, current versus never-smoking was associated with unexpected 2.3-fold risk of ulcerative colitis and expected 1.9-fold risk of Crohn's disease in prospective analyses; however, genetic evidence of lifelong increased smoking intensity did not support causal relationships.

BackgroundSmoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.MethodsWe analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.ResultsMeta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.ConclusionsRare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

Objective- Whether tobacco smoking causally affects white and red blood cells and thrombocyte counts is unknown. Using a Mendelian randomization approach, we tested the hypothesis that smoking causes increases in these blood cell indices. Approach and Results- We included 104 607 white Danes aged 20 to 100 years from the Copenhagen General Population Study with information on blood cell indices, smoking habits, and CHRNA3 (alpha 3 nicotinic cholinergic receptor) rs1051730 genotype, where the T allele causes higher tobacco consumption; 41 759 were former smokers and 17 852 current smokers. In multivariable adjusted observational analyses and compared with never smokers, white blood cells were associated with up to 19% increases, thrombocytes with up to 4.7% increases, and red blood cell indices with up to 2.3% increases in former and current smokers. All associations were dose dependent, with tobacco consumption but for white blood cells and thrombocytes also dependent on smoking cessation time in former smokers; highest increases were for1-year smoking cessation and lowest increases for10-year smoking cessation. In age- and sex-adjusted genetic analyses, percent differences per T allele increase in current smokers were 1.15% (95% CI, 0.61%-1.68%) for leukocytes, 1.07% (0.38%-1.76%) for neutrophils, 1.34% (0.66%-2.02%) for lymphocytes, 1.50% (0.83%-2.18%) for monocytes, -0.60% (-1.91% to 0.74%) for eosinophils, 0.17% (-0.94% to 1.29%) for basophils, 0.38% (-0.17% to 0.93%) for thrombocytes, 0.04% (-0.14% to 0.23%) for erythrocytes, 0.34% (0.17% to 0.50%) for hematocrit, 0.26% (0.09% to 0.43%) for hemoglobin, and 0.29% (0.18% to 0.41%) for mean corpuscular volume. Conclusions- Smoking causes increased blood leukocytes, neutrophils, lymphocytes, and monocytes, as well as increased hematocrit, hemoglobin, and mean corpuscular volume. The observational smoking relationships were long term for white blood cells and short term for red blood cell indices.

International recommendations state that reference values for lung function should derive from cross-sectional studies of healthy nonsmokers and be renewed from time to time because of cohort effect and newer, more accurate, technical equipment. In 1986, the Danish Lung Society published reference values for spirometry based on 570 individuals aged 30-70 years.To produce new reference values for lung function and to extend the existing values by including individuals between 20 and 30 years of age and older than 70 years of age.Two similar but independent studies was used: The 2001-2003 examination of the Copenhagen City Heart Study and the 2003–2010 examination of the Copenhagen General Population Study. Of a total of 69 822 individuals, we included 11 288 healthy never-smoking white individuals to produce the reference values: 6307 women and 4981 men, 20 years of age or older with adequate lung function.We used sex-stratified multiple linear regression analysis to find prediction formulas for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC adjusted for age and height. The cutoff value of normal lung function was defined as the fifth percentile (also named the 5% quantile) according to gender, age and height. The robustness of the data was tested and validated in several ways.Compared with the 1986 data, our 2001–2010 material contributes with a substantial number of individuals in the more extreme groups of age and height, and in general, our dataset shows that in most subgroups, the lung function level has improved during the last two decades.

The importance of coronary heart disease risk factors may differ between individuals and community and by sex and age.The Copenhagen City Heart Study followed for 21 years a random sample of 5599 men and 6478 women aged 30 to 79 years at baseline. The importance of risk factors in individuals and the community were evaluated as relative and population attributable risks.We traced 2180 coronary events. In Cox regression analysis with ten risk factors entered simultaneously, relative risks for coronary heart disease in men ranged from 1.69 to 1.20 with the highest risks for diabetes, hypertension, smoking, and physical inactivity. In women, relative risks ranged from 2.74 to 1.19 with the highest risks for diabetes, smoking, hypertension, and physical inactivity. Population attributable risks in men ranged from 22 to 3% with the highest risks for smoking, hypertension, and no daily alcohol intake. In women, attributable risks ranged from 37 to 3% with the highest risks for smoking, hypertension, and hypercholesterolemia. Several of these rankings differed by age.The importance of coronary heart disease risk factors may differ for individuals, the community, and by sex and age. Consequently, prevention strategies should be tailored accordingly.

Our goal was to estimate the number of individuals with chronic obstructive pulmonary disease (COPD) in the Capital Region of Denmark and the need of resources required to implement the regional management programme for COPD.We examined a total of 45,970 participants from the Copenhagen General Population Study (CGPS) using spirometry and a questionnaire.The prevalence of spirometrically defined COPD among individuals older than 40 years of age was 15%, corresponding to 120,000 citizens in the Region. The number of individuals with moderate COPD (forced expiratory volume in one second (FEV1): 50-80% of predicted value) was estimated to approx. 51,000 (6.4%), whereas at least 10,000 (1.3%) were expected to have severe or very severe COPD (FEV150% of predicted value). Our estimates indicate that more than 26,000 individuals with moderate, severe or very severe COPD in the Region are smokers and that more than 19,000 qualify for physical training. We estimated that approx. 4,000 individuals with severe COPD were not treated with any inhaled medication.The Capital Region of Denmark needs to allocate substantial resources into early detection, rehabilitation and medical treatment of individuals with COPD in order to comply with the intentions of the Region's own management programme for COPD.The present analyses were sponsored by a grant from the Danish Ministry of Health. The CGPS was supported by the Copenhagen County Foundation, the Danish Medical Research Council and the Boserup Foundation.not relevant.