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Introduction: Thorough assessment of the antiphospholipid syndrome (APS) includes retesting of positive antiphospholipid antibody (aPL) tests after at least 12 weeks, and a full antiphospholipid antibody profile. To what extent this work-up is done in clinical practice is unknown., Methods: Data on 25 116 in- and out-hospital patients tested for the presence of lupus anticoagulant (LA), the aPL which most strongly correlates with thrombosis, was extracted from the laboratory information system of the only laboratory that performs LA tests in the Capital Region, Denmark. We estimated fraction of repeated tests, tests repeated within the recommended time span, and fraction with a full aPL profile., Results: Out of 25 116 patients, 843 were positive for LA (3.3%), and 3948 results were inconclusive (16%). Only 51% (95% CI of the proportion: 48%-54%) (n = 431) of positive tests were repeated. The proportion of inconclusive LA test results increased from 13% (12%-15%) in 2009 to 20% (19%-22%) in 2020. Out of the positive tests repeated within the first year, only 60/353 (17%; 13%-21%) were repeated within 12-16 weeks; 177/353 (50%; 45%-55%) were re-tested within the first 12 weeks of first positive test result. The proportion of patients with a full antiphospholipid antibody profile increased from 161/1978 (8%) in 2010 to 1041/1978 (43%) in 2020., Conclusion: We found several issues with the laboratory workup of APS. This indicates a need for increased awareness of comprehensive laboratory assessment of possible APS as well as a closer collaboration between the laboratory and clinicians., (© 2024 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Background: It is unknown if an unhealthy diet can affect the risk of developing psoriasis., Objectives: We hypothesised that individuals with an unhealthy diet have increased risk of prevalent and incident psoriasis., Methods: We included 105,332 adults from the Copenhagen General Population Study, who were invited between 2003 and 2015. Response-rate was 43%. An unhealthy versus healthy diet was defined according to adherence to general national dietary guidelines. The participants were grouped into low, intermediate, and high adherence to general national dietary guidelines based on information from a food frequency questionnaire. Identification of psoriasis was made using ICD codes., Results: Of the 105,332 individuals, 580 had a diagnosis of psoriasis at the time of enrolment and 640 received a diagnosis during the median follow-up of 9 years. Risk of prevalent psoriasis increased according to non-adherence to general national dietary guidelines in a stepwise manner with an age and sex adjusted odds ratio of 1.70 (95% confidence interval 1.26-2.30) in individuals with low vs. high adherence to dietary guidelines. Results were similar in a multivariable adjusted model. Prospective analyses adjusted for age and sex showed a weak association between non-adherence to dietary guidelines and risk of incident psoriasis (P for trend 0.04). This association disappeared, when adjusting for multiple confounders (P for trend 0.50)., Conclusions: Although individuals with psoriasis have an unhealthier diet, diet alone does not appear to independently increase the risk of developing psoriasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Psoriasis is associated with high alcohol consumption, but the causality of this relationship is unclear., Objective: We aimed to use a Mendelian randomization approach to investigate the causal effects of alcohol on incident psoriasis., Methods: We included 102,655 adults from the prospective Copenhagen studies. All participants filled out a questionnaire on alcohol consumption, were physically examined, and had blood drawn for biochemical and genetic analyses. We created a genetic instrument based on the number of fast-metabolizing alleles in alcohol dehydrogenase 1B and alcohol dehydrogenase 1C, known to be associated with alcohol consumption, to test whether alcohol consumption was causally associated with psoriasis., Results: Observationally, we found an increased risk of incident psoriasis among individuals with high alcohol consumption compared to those with low alcohol consumption with a hazard ratio of 1.30 (95% confidence interval 1.05-1.60) in the fully adjusted model. Using genetic data to predict alcohol consumption to avoid confounding and reverse causation, we found no association between number of fast-metabolizing alleles and risk of psoriasis., Limitations: Alcohol consumption was self-reported and psoriasis was defined using the International Classification of Diseases 10th revision and 8th revision codes., Conclusion: Alcohol consumption is observationally but not causally associated with incident psoriasis., Competing Interests: Jordan, Dr Vedel-Krogh, and Bojesen report no conflicts of interest. Dr Näslund-Koch has served as an investigator for Galderma, AbbVie, LEO Pharma, Novartis, and CSL Behring. Skov has received research funding from Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the LEO Foundation and the Kgl Hofbundtmager Aage Bang Foundation and honoraria as consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, and LEO Pharma, Janssen, UCB, Almirall, Bristol-Myers Squibb, and Sanofi. She has served as an investigator for AbbVie, Pfizer, Sanofi, Janssen, Boehringer Ingelheim, AstraZeneca, Eli Lilly, Novartis, Regeneron, Galderma, and LEO Pharma., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Purpose of Review: The aim of this study is to summarize major cardiovascular guideline recommendations on lipoprotein(a) and highlighting recent findings that emphasize how measuring lipoprotein(a) once in all adults is meaningful regardless of age, sex, comorbidities, or ethnicity., Recent Findings: Many international guidelines now recommend once in a lifetime measurement of lipoprotein(a) in all adult individuals to facilitate accurate risk prediction. Lipoprotein(a)-lowering therapy to reduce cardiovascular disease is on the horizon, with results from the first phase 3 trial expected in 2025., Summary: Elevated lipoprotein(a) is an independent causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis and measuring lipoprotein(a) once in all individuals regardless of age, sex, comorbidities, or ethnicity is meaningful to aid in risk stratification., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lp(a) (lipoprotein[a])-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal aortic aneurysms (AAAs), and major adverse limb events (MALE)., Objectives: The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE., Methods: The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study., Results: Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend <0.001). For individuals with Lp(a) levels ≥99th (≥143 mg/dL, ≥307 nmol/L) vs <50th percentile (≤9 mg/dL, ≤17 nmol/L), multivariable-adjusted HRs were 2.99 (95% CI: 2.09-4.30) for PAD and 2.22 (95% CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95% CI: 1.55-5.98). Per 50 mg/dL (105 nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95% CI: 1.24-1.56) for PAD and 1.21 (95% CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95% CI: 1.24-1.43) and 1.27 (95% CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a) <50th and ≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men., Conclusions: High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies., Competing Interests: Funding Support and Author Disclosures The study was founded by the Department of Clinical Biochemistry, Copenhagen University Hospital–Herlev and Gentofte, Gangstedfonden, and was supported by a research grant from the Danish Cardiovascular Academy (grant number 2022007-HF), which is funded by the Novo Nordisk Foundation, grant number NNF20SA0067242 and The Danish Heart Foundation. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the paper, or decision to submit the manuscript for publication. Dr Nordestgaard has consultancies with Abbott, Akcea, Amarin, Amgen, AstraZeneca, Denka, Esperion, Kowa, Lilly, Mankind, Novartis, Novo Nordisk, Regeneron, Sanofi, Silence Therapeutics, and Ultragenyx. Dr Kamstrup has lecture honoraria or consultancies from Physicians’ Academy for Cardiovascular Education, PCSK9 Forum, Silence Therapeutics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: It is unclear whether higher triglyceride metabolism per se contributes to mortality separate from elevated triglyceride-rich lipoproteins and body mass index. This study tested the hypotheses that higher triglyceride metabolism, measured as higher plasma glycerol and β-hydroxybutyrate, is associated with increased all-cause, cardiovascular, cancer, and other mortality., Methods and Results: This study included 30 000 individuals nested within 109 751 individuals from the Copenhagen General Population Study. During a median follow-up of 10.7 years, 9897 individuals died (2204 from cardiovascular, 3366 from cancer, and 2745 from other causes), while none were lost to follow-up. In individuals with glycerol >80 µmol/L (highest fourth) vs. individuals with glycerol <52 µmol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.31 (95% confidence interval 1.22-1.40). In individuals with β-hydroxybutyrate >154 µmol/L (highest fourth) vs. individuals with β-hydroxybutyrate <91 µmol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.18 (1.11-1.26). Corresponding values for higher plasma glycerol and β-hydroxybutyrate were 1.37 (1.18-1.59) and 1.18 (1.03-1.35) for cardiovascular mortality, 1.24 (1.11-1.39) and 1.16 (1.05-1.29) for cancer mortality, and 1.45 (1.28-1.66) and 1.23 (1.09-1.39) for other mortality, respectively. Results were robust to exclusion of first years of follow-up, to stratification for covariates including plasma triglycerides and body mass index, and to further adjustments., Conclusion: This study observed an increased risk of all-cause, cardiovascular, cancer, and other mortality with higher triglyceride metabolism. This was not explained by higher plasma triglycerides and body mass index. The hypothesis studied in the present paper should be further validated by isotope flux studies., Competing Interests: Conflict of interest B.G.N. reports consultancies and talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. G.D.S. reports Scientific Advisory Board Membership for Relation Therapeutics and Insitro. There are no financial or other conflicts of interest for M.Ø.J., S.A., S.V.-K., or S.F.N., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels., Methods and Results: A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st-100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st-33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43-1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36-1.82) for those with C-reactive protein ≥2 mg/l (P for interaction = 0.87). The corresponding values were 2.08 (1.76-2.45) and 1.65 (1.34-2.04) for myocardial infarction, and 2.01 (1.59-2.55) and 1.73 (1.31-2.27) for aortic valve stenosis, respectively (P for interaction = 0.15 and = 0.18). The highest absolute 10-year risks were found in men aged 70-79 years with lipoprotein(a) levels in the 91st-100th percentiles and C-reactive protein ≥2 mg/l, with 34% for ASCVD, 19% for myocardial infarction, and 13% for aortic valve stenosis. The corresponding values in women were 20%, 10%, and 8%, respectively., Conclusion: High lipoprotein(a) was a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis independent of C-reactive protein levels., Competing Interests: Conflicts of interest: B.G.N. reports consultancies with Akcea, Amarin, Amgen, AstraZeneca, Denka, Kowa, Novartis, Novo Nordisk, Sanofi, Regeneron, Esperion, and Silence Therapeutics. P.R.K. reports lecture honoraria or consultancies from Physicians’ Academy for Cardiovascular Education, Silence Therapeutics, and Novartis. P.E.T. and S.V.-K. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Smoking is strongly associated with higher risk of psoriasis in several observational studies; however, whether this association is causal or can be explained by confounding or reverse causation is not fully understood. Randomized controlled trials are the gold standard when examining causality; however, when this method is not feasible, the Mendelian randomization design is an alternative. Herein genetic variants can be used as robust proxies for modifiable exposures and thereby avoiding confounding and reverse causation.In this study, we hypothesized that smoking is an independent and causal risk factor for psoriasis and tested this using a Mendelian randomization design., Methods: We used data from the Copenhagen General Population Study including 105,912 individuals with full information on lifestyle factors, biochemistry, and genotype data. In total, 1,240 cases of moderate to severe psoriasis were included to investigate the association between smoking and psoriasis. To assess causality of the association, we used the genetic variant CHRNA3 rs1051730, where the T-allele is strongly associated with high lifelong cumulative smoking, as a proxy for smoking., Results: In observational analyses, the multivariable adjusted hazard ratio of developing moderate to severe psoriasis was 1.64 (95% confidence interval: 1.35-2.00) in ever smokers with ≤ 20 pack-years and 2.23 (1.82-2.73) in ever smokers with > 20 pack-years compared to never smokers. In genetic analyses, the odds ratio of developing moderate to severe psoriasis was 1.05 (0.95-1.16) per CHRNA3 rs10511730 T-allele in ever smokers., Conclusion: Smoking was an independent risk factor for moderate to severe psoriasis in observational analyses. However, using a genetic variant as a robust proxy for smoking, we did not find this association to be causal., Competing Interests: CN-K has served as an investigator for Galderma, Abbvie, LEO Pharma, and CSL Behring. LS has served as an investigator for AbbVie, Pfizer, Sanofi, Janssen Cilag, Boehringer Ingelheim, AstraZeneca, Eli Lilly, Novartis, Regeneron, Galderma and LEO Pharma. LS has received research funding from Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the LEO Foundation, and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, and LEO Pharma, Janssen Cilag, UCB, Almirall, Bristol-Myers Squibb, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Näslund-Koch, Vedel-Krogh, Bojesen and Skov.)

Background: Psoriasis is observationally associated with a higher risk of non-alcoholic fatty liver disease (NAFLD); however, the causal relationship between the two diseases remains unclear., Objective: We hypothesized that individuals with NAFLD or elevated liver fat content have higher risk of psoriasis and that NAFLD is a causal risk factor for psoriasis. We tested this using a Mendelian randomization approach., Methods: We included 108,835 individuals from the Danish general population, including 1,277 individuals with psoriasis and 802 individuals with NAFLD according to ICD codes. To estimate liver fat content, a subset of the participants (N = 7,416) also had a CT scan performed. First, we tested whether a diagnosis of NAFLD or elevated liver fat content was observationally associated with risk of psoriasis. Subsequently, we used the genetic variants PNPLA3 and TM6SF2 , both strongly associated with NAFLD and high liver fat content, to test whether NAFLD was causally associated with increased risk of psoriasis., Results: Observationally, individuals with vs. without a diagnosis of NAFLD had higher risk of psoriasis with an odds ratio of 2.03 (95% confidence interval 1.28-3.21). The risk of psoriasis increased in a stepwise manner with increasing liver fat content with an odds ratio of 5.00 (2.63-9.46) in individuals in the highest quartile of liver fat content compared to individuals in the lowest quartile. In genetic analyses, PNPLA3 and TM6SF2 were both associated with increased risk of NAFLD but not with increased risk of psoriasis., Conclusion: Observationally, a diagnosis of NAFLD or elevated liver fat content was associated with higher risk of psoriasis. However, using genetic variants as a proxy for NAFLD, we did not find evidence of a causal relationship between NAFLD and psoriasis. Thus, the observational association between NAFLD and psoriasis is presumably a result of shared confounding factors or reverse causation., Competing Interests: CN-K has served as an investigator for Galderma, Abbvie, LEO Pharma, and CSL Behring. LS has received research funding from Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the LEO Foundation and the Kgl Hofbundtmager Aage Bang Foundation and honoraria as consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, and LEO Pharma, Janssen, UCB, Almirall, Bristol-Myers Squibb, and Sanofi. LS has served as an investigator for AbbVie, Pfizer, Sanofi, Janssen, Boehringer Ingelheim, AstraZeneca, Eli Lilly, Novartis, Regeneron, Galderma and LEO Pharma. LG has received research funding from Novo Nordisk, Alexion, Gilead, Vingmed and honoraria as consultant/speaker/expert testimony from Novo Nordisk, Pfizer, Sobi International, and Norgine. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Näslund-Koch, Bojesen, Gluud, Skov and Vedel-Krogh.)

Women with cardiovascular disease are underdiagnos-ed, undertreated and under-represented in research. Even though the increased risk of cardiovascular disease among patients with psoriasis is well establi-shed, only a few studies have examined women with psoriasis. This study examined the prevalence of cardio-vascular risk factors and cardiovascular disease among women with psoriasis. Using the Copenhagen City Heart Study and the Copenhagen General Population Study, 66,420 women were included in a cross-sectional design. Of these, 374 (0.56%) women had hospital-diagnosed psoriasis. Women with vs with-out hospital-diagnosed psoriasis had higher odds ratios of having traditional cardiovascular risk factors, including hypertriglyceridaemia, smoking, obesity, type 2 diabetes, and low physical activity, and of having non-traditional cardiovascular risk factors, including low level of education, high level of psycho-social stress, and low-grade inflammation. Compared with women from the general population, the multi-variable adjusted odds ratio of heart failure and ischaemic cerebrovascular disease in women with hospital-diagnosed psoriasis was 2.51 (95% confidence interval 1.33-4.73) and 2.06 (1.27-3.35). In conclusion, women with hospital-diagnosed psoriasis have a higher prevalence of traditional and non- traditional cardiovascular risk factors, and increased risk of heart failure and ischaemic cerebrovascular disease, even after adjusting for these cardiovascular risk factors.

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., (© 2021. Springer Nature B.V.)

Background: Asthma and COPD diagnoses are used to classify chronic airway diseases; however, both diseases are related to phenotypic traits like allergy, obesity, cough, sputum production, low-grade inflammation, smoking, elevated blood eosinophil count, comorbidities, and occupational exposures. Whether such traits can replace asthma and COPD diagnoses when assessing risk of exacerbation is unclear. We tested the hypothesis that individuals with either asthma or COPD diagnoses have similar risk of moderate and severe exacerbations when adjusted for differences in phenotypic traits., Methods: From the Copenhagen General Population Study, a cohort study of the general population, we included 7190 individuals with chronic airway disease. Phenotypic traits were recorded at baseline and risk of exacerbations was assessed during follow-up from 2003 to 2013., Results: The incidence rate ratio (IRR) of moderate exacerbations in individuals with clinical COPD was 1.61 (95% Confidence Interval, 1.27-2.02) compared to individuals with asthma in a model only adjusted for age, sex, and education, but after the inclusion of phenotypic traits IRR was 1.05 (0.82-1.35). Corresponding IRRs of severe exacerbations in individuals with clinical COPD versus asthma were 3.82 (2.73-5.35) and 2.28 (1.63-3.20), respectively., Conclusions: When taking phenotypic traits into account, individuals with asthma and COPD had comparable risk of moderate exacerbations; however, corresponding risk of severe exacerbations was higher in individuals with COPD than in those with asthma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration is associated with high risks of asthma hospitalisation and exacerbation.We prospectively assessed the risk of asthma hospitalisation in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608 and rs448260 determining levels of complement C3. Risk of asthma exacerbation was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisation was 1.23 (95% CI 1.04-1.45) for individuals in the highest tertile (>1.19 g·L -1 ) of plasma complement C3 compared with those in the lowest tertile (<1.03 g·L -1 ). The C3 rs448260 genotype was associated with risk of asthma hospitalisation with an observed hazard ratio of 1.17 (95% CI 1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE (p for trends ≤6×10 -9 ), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count (p=3×10 -4 ) and IgE level (p=3×10 -4 ). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbation was 1.69 (95% CI 1.06-2.72) for individuals in the highest plasma complement C3 tertile (>1.24 g·L -1 ) versus the lowest (<1.06 g·L -1 ).In conclusion, a high concentration of plasma complement C3 was associated with a high risk of asthma hospitalisation in the general population and with a high risk of asthma exacerbation in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity., Competing Interests: Conflict of interest: S. Vedel-Krogh has nothing to disclose. Conflict of interest: K.L. Rasmussen has nothing to disclose. Conflict of interest: B.G. Nordestgaard has nothing to disclose. Conflict of interest: S.F. Nielsen has nothing to disclose., (Copyright ©ERS 2021.)

Background: Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL) cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity., Methods: We included 29 010 individuals free of myocardial infarction at baseline, nested within 109 751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy., Results: Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%)., Conclusions: VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin., Methods: We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption., Results: In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers., Conclusion: Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal., Implications: Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: We aimed to test the hypothesis that levels of total and low-density lipoprotein cholesterol are increased after Christmas and that the risk of hypercholesterolemia is increased after the Christmas holidays., Methods: We conducted an observational study of 25,764 individuals from the Copenhagen General Population Study, Denmark, aged 20-100 years. Main outcome measures were mean total and LDL cholesterol levels. Hypercholesterolemia was defined as total cholesterol >5 mmol/L (>193 mg/dL) or LDL-cholesterol >3 mmol/L (>116 mg/dL)., Results: Mean levels of total and LDL cholesterol increased in individuals examined in summer through December and January. Compared with individuals examined in May-June, those examined in December-January had 15% higher total cholesterol levels (p < 0.001). The corresponding value for LDL cholesterol was 20% (p < 0.001). Of the individuals attending the study during the first week of January, immediately after the Christmas holidays, 77% had LDL cholesterol above 3 mmol/L (116 mg/dL) and 89% had total cholesterol above 5 mmol/L (193 mg/dL). In individuals attending the Copenhagen General Population Study in the first week of January, the multivariable adjusted odds ratio of hypercholesterolemia was 6.0 (95% confidence interval 4.2-8.5) compared with individuals attending the study during the rest of the year., Conclusions: Celebrating Christmas is associated with higher levels of total and LDL cholesterol and a higher risk of hypercholesterolemia in individuals in the general population. Thus, a diagnosis of hypercholesterolemia should not be made around Christmas, and our results stress the need for re-testing such patients later and certainly prior to initiation of cholesterol-lowering treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Context: Vitamin D may be a modifiable risk factor for inflammatory bowel disease (IBD)., Objectives: We tested the hypothesis that plasma 25-hydroxyvitamin D levels are causally associated with risk of Crohn disease (CD) and ulcerative colitis (UC)., Design, Setting, Patients, and Interventions: We used a Mendelian randomization design to study 120,013 individuals from the Copenhagen City Heart Study, the Copenhagen General Population Study, and a Copenhagen-based cohort of patients with IBD. Of these, 35,558 individuals had plasma 25-hydroxyvitamin D measurements available, and 115,110 were genotyped for rs7944926 and rs11234027 in DHCR7 and rs10741657 and rs12794714 in CYP2R1, all variants associated with plasma 25-hydroxyvitamin D levels. We identified 653 cases of CD and 1265 cases of UC, of which 58 and 113, respectively, had 25-hydroxyvitamin D measurements available. We also included genetic data from 408,455 individuals from the UK Biobank, including 1707 CD cases and 3147 UC cases., Main Outcome Measure: Hazard ratios for higher plasma 25-hydroxyvitamin D levels., Results: The multivariable-adjusted hazard ratios for 10 nmol/L higher 25-hydroxyvitamin D level were 1.04 (95% CI: 0.93 to 1.16) for CD and 1.13 (95% CI: 1.06 to 1.21) for UC. A combined 25-hydroxyvitamin D allele score was associated with a 1.4-nmol/L increase in plasma 25-hydroxyvitamin D level and hazard ratios of 0.98 (95% CI: 0.94 to 1.03) for CD and 1.01 (95% CI: 0.97 to 1.05) for UC. Combining genetic data from the Copenhagen studies and the UK Biobank, genetically determined vitamin D did not appear to influence the risk of CD or UC., Conclusions: Our results do not support a major role for vitamin D deficiency in the development of IBD.

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 FEV 1 % 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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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).

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 (FEV 1 ) <50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded.Among individuals with COPD and FEV 1 <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 ≥0.34×10 9  cells·L -1 versus <0.34×10 9  cells·L -1 In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV 1 <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 FEV 1 ≥50% pred.In individuals with COPD and FEV 1 <50% pred, blood eosinophil count ≥0.34×10 9  cells·L -1 was associated with high risk of hospitalisation due to pneumonia., Competing Interests: Conflict of interest: J. Vestbo has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, GlaxoSmithKline and Novartis, outside the submitted work. Conflict of interest: P. Lange has received grants and personal fees from Almirall, AstraZeneca, Boehringer Ingelheim, Novartis and GlaxoSmithKline, and personal fees from Norpharma, Takeda and Pfizer, outside the submitted work., (Copyright ©ERS 2018.)

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 (FEV 1 ) after multivariable adjustment including smoking. Hypomethylation was also associated with a lower z-score for both forced vital capacity (FVC) and FEV 1 /FVC. In prospective analyses, individuals in the lowest versus highest tertile of methylation extent had a steeper decline in FEV 1 /height 3 (p for examination×methylation interaction=0.003) and FVC/height 3 (p=0.01), but not FEV 1 /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., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

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 FEV 1 and FEV 1 /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 FEV 1 /FVC) but no effect on longitudinal decline (p=0.160 for FEV 1 /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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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 × 10 9 /L (highest tertile) vs individuals with blood eosinophil counts <0.18 × 10 9 /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 × 10 9 /L (highest tertile) vs individuals with blood neutrophil counts <3.77 × 10 9 /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., (© 2016 American Association for Clinical Chemistry.)

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.

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.

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.

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.