Complement C3 and allergic asthma: A cohort study of the general population

2020 ◽  
pp. 2000645
Author(s):  
Signe Vedel-Krogh ◽  
Katrine L. Rasmussen ◽  
Børge G. Nordestgaard ◽  
Sune F. Nielsen
Keyword(s):  
High Risk ◽  
General Population ◽  
Allergic Asthma ◽  
High Plasma ◽  
Hazard Ratio ◽  
Complement C3 ◽  
Blood Eosinophil ◽  
High Concentration ◽  
General Population Study ◽  
Asthma Exacerbations

Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration was associated with high risk of asthma hospitalisations and exacerbations.We prospectively assessed the risk of asthma hospitalisations 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 exacerbations was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisations was 1.23(95% confidence interval 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 hospitalisations with an observed hazard ratio of 1.17(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 level of IgE(p=3·10−4). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbations was 1.69(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, high concentration of plasma complement C3 was associated with high risk of asthma hospitalisations in the general population and with high risk of asthma exacerbations in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity.

scholarly journals Association of Blood Eosinophil and Blood Neutrophil Counts with Asthma Exacerbations in the Copenhagen General Population Study

2017 ◽  
Vol 63 (4) ◽  
pp. 823-832 ◽  
Author(s):  
Signe Vedel-Krogh ◽  
Sune Fallgaard Nielsen ◽  
Peter Lange ◽  
Jørgen Vestbo ◽  
Børge Grønne Nordestgaard
Keyword(s):  
General Population ◽  
Disease Severity ◽  
Population Study ◽  
Blood Eosinophil ◽  
Blood Neutrophil ◽  
General Population Study ◽  
Asthma Exacerbations ◽  
Increased Risk ◽  
Blood Neutrophils ◽  
Eosinophil Counts

Abstract 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 &gt;0.29 × 109/L (highest tertile) vs individuals with blood eosinophil counts &lt;0.18 × 109/L (lowest tertile). For blood neutrophils, the multivariable-adjusted IRRs were 2.14 (1.74–2.63) for moderate exacerbations and 1.18 (0.89–1.55) for severe exacerbations for individuals with blood neutrophil counts &gt;4.85 × 109/L (highest tertile) vs individuals with blood neutrophil counts &lt;3.77 × 109/L (lowest tertile). Blood eosinophil and neutrophil counts interacted on moderate exacerbations (P = 3 × 10−4), but not on severe exacerbations. CONCLUSIONS High blood eosinophil counts are associated with an increased risk of both moderate and severe asthma exacerbations, while high blood neutrophil counts are associated with an increased risk of moderate, but not severe exacerbations.

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

2018 ◽  
Vol 51 (5) ◽  
pp. 1800120 ◽  
Author(s):  
Signe Vedel-Krogh ◽  
Børge G. Nordestgaard ◽  
Peter Lange ◽  
Jørgen Vestbo ◽  
Sune F. Nielsen
Keyword(s):  
High Risk ◽  
General Population ◽  
Eosinophil Count ◽  
Inhaled Corticosteroids ◽  
Chronic Obstructive ◽  
Blood Eosinophil ◽  
Exacerbation Rate ◽  
General Population Study ◽  
Blood Eosinophil Count ◽  
Eosinophil Counts

Blood eosinophil count in chronic obstructive pulmonary disease (COPD) is associated with higher exacerbation rate and favourable response to corticosteroids; however, frequent exacerbations and use of inhaled corticosteroids could elevate pneumonia risk. We tested the hypothesis that high blood eosinophil counts are associated with high risk of pneumonia in individuals with severe COPD from the general population.We included 7180 individuals with COPD from the Copenhagen General Population Study, including 643 with forced expiratory volume in 1 s (FEV1) <50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded.Among individuals with COPD and FEV1<50% pred, the multivariable adjusted incidence rate ratio was 2.17 (95% CI 1.31–3.58) for pneumonia comparing individuals with blood eosinophil counts ≥0.34×109 cells·L−1versus<0.34×109 cells·L−1. In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV1<70% pred, the corresponding risk was 4.52 (2.11–9.72). Risk of pneumonia did not differ by blood eosinophil count in individuals with COPD and FEV1≥50% pred.In individuals with COPD and FEV1<50% pred, blood eosinophil count ≥0.34×109 cells·L−1was associated with high risk of hospitalisation due to pneumonia.

scholarly journals Complement C3 and High Risk of Venous Thromboembolism: 80517 Individuals from the Copenhagen General Population Study

2016 ◽  
Vol 62 (3) ◽  
pp. 525-534 ◽  
Author(s):  
Ina Nørgaard ◽  
Sune F Nielsen ◽  
Børge G Nordestgaard
Keyword(s):  
Pulmonary Embolism ◽  
Venous Thromboembolism ◽  
High Risk ◽  
General Population ◽  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Population Study ◽  
Mean Value ◽  
Complement C3 ◽  
General Population Study

Abstract BACKGROUND Complement activation may contribute to venous thromboembolism, including deep venous thrombosis and pulmonary embolism. We tested the hypothesis that high complement C3 concentrations are associated with high risk of venous thromboembolism in the general population. METHODS We included 80 517 individuals without venous thromboembolism from the Copenhagen General Population Study recruited in 2003–2012. Plasma complement C3 concentrations were measured at baseline, and venous thromboembolism (n = 1176) was ascertained through April 2013 in nationwide registries. No individuals were lost to follow-up. RESULTS Complement C3 concentrations were approximately normally distributed, with a mean value of 1.13 g/L (interquartile range 0.98–1.26; SD 0.21). The cumulative incidence of venous thromboembolism was higher with progressively higher tertiles of complement C3 (log-rank trend: P = 3 × 10−8): at age 80, 7%, 9%, and 11% of individuals in the first, second, and third tertiles, respectively, had developed venous thromboembolism. Multivariable-adjusted hazard ratios for venous thromboembolism compared with individuals in the first tertile were 1.36 (95% CI, 1.16–1.59) for those in the second tertile and 1.58 (1.33–1.88) for those in the third tertile. Corresponding values were 1.36 (1.16–1.60) and 1.57 (1.33–1.87) after additional adjustment for C-reactive protein and 1.27 (1.09–1.49) and 1.31(1.10–1.57) after additional adjustment for body mass index. These results were similar for deep venous thrombosis and pulmonary embolism separately. The multivariable-adjusted hazard ratio for venous thromboembolism for a 1-g/L increase in complement C3 was 2.43 (1.74–3.40). CONCLUSIONS High concentrations of complement C3 were associated with high risk of venous thromboembolism in the general population.

scholarly journals Left ventricular myocardial crypts: morphological patterns and prognostic implications

2020 ◽  
Vol 22 (1) ◽  
pp. 75-81 ◽  
Author(s):  
Per E Sigvardsen ◽  
Michael H C Pham ◽  
Jørgen T Kühl ◽  
Andreas Fuchs ◽  
Shoaib Afzal ◽  
...  
Keyword(s):  
General Population ◽  
Cardiovascular Events ◽  
Cox Regression ◽  
Cardiac Computed Tomography ◽  
Left Ventricular ◽  
Specific Pattern ◽  
Hazard Ratio ◽  
Major Adverse Cardiovascular Events ◽  
General Population Study ◽  
Myocardial Crypts

Abstract Aims  Left ventricular (LV) myocardial crypts are considered a subtle marker of hypertrophic cardiomyopathy. However, crypts have also been observed in seemingly healthy individuals and it is unknown whether myocardial crypts are associated with adverse outcome. Methods and results  Myocardial crypts were defined as invaginations traversing &gt;50% of the myocardial wall and assessed using contrast-enhanced cardiac computed tomography in 10 097 individuals from the Copenhagen General Population Study. Number of crypts, location, shape, penetrance, and volume were assessed. The endpoint was a composite of major adverse cardiovascular events and defined as death, myocardial infarction, heart failure, or stroke. Cox regression models were adjusted for clinical variables, medical history, electrocardiographic parameters, and cardiac chamber sizes. A total of 1199 LV myocardial crypts were identified in 915 (9.1%) individuals. Seven hundred (6.9%) had one crypt and 215 (2.1%) had multiple crypts. During a median follow-up of 4.0 years (interquartile range 1.5–6.7), major adverse cardiovascular events occurred in 619 individuals. Individuals with one or multiple crypts had a hazard ratio for major adverse cardiovascular events of 1.00 [95% confidence interval (CI): 0.72–1.40; P = 0.98] and 0.90 (95% CI: 0.47–1.75; P = 0.76), respectively, compared with those with no crypts. No specific pattern of crypt location, shape, penetrance, or volume was associated to an increased hazard ratio for major adverse cardiovascular events. Conclusion  LV myocardial crypts are frequent in the general population and are not associated with intermediate-term major adverse cardiovascular events.

scholarly journals High Lipoprotein(a) and Low Risk of Major Bleeding in Brain and Airways in the General Population: a Mendelian Randomization Study

2017 ◽  
Vol 63 (11) ◽  
pp. 1714-1723 ◽  
Author(s):  
Anne Langsted ◽  
Pia R Kamstrup ◽  
Børge G Nordestgaard
Keyword(s):  
Wound Healing ◽  
General Population ◽  
Major Bleeding ◽  
Human Genetics ◽  
Physiological Role ◽  
Hazard Ratio ◽  
Low Risk ◽  
General Population Study ◽  
Lipoprotein A ◽  
The Brain

Abstract BACKGROUND The physiological role of lipoprotein(a) is unclear; however, lipoprotein(a) may play a role in hemostasis and wound healing. We tested the hypothesis that high lipoprotein(a) concentrations are associated with low risk of major bleeding in the brain and airways both observationally and causally (from human genetics). METHODS We examined 109169 individuals from the Copenhagen City Heart Study and the Copenhagen General Population study, 2 similar prospective studies conducted in the Danish general population. Individuals had information on plasma lipoprotein(a) concentrations (n = 59980), LPA kringle-IV type 2 (KIV-2) number of repeats (n = 98965), and/or LPA single-nucleotide polymorphism rs10455872 associated with high lipoprotein(a) concentrations (n = 109 169), and information on hospital contacts or death due to major bleeding in brain and airways from registers. RESULTS Using extreme phenotypes or genotypes, the multifactorially adjusted hazard ratio for major bleeding in the brain and airways was 0.84 (95%CI: 0.71–0.99) for lipoprotein(a), &gt;800 mg/L vs &lt;110 mg/L; 0.83 (0.73–0.96) for KIV-2, &lt;24 vs &gt;35 number of repeats; and 0.89 (0.81–0.97) for rs10455872 carriers (heterozygotes + homozygotes) vs noncarriers. The corresponding hazard ratios were 0.89 (0.82–0.98) for heterozygotes and 0.59 (0.36–0.98) for homozygotes separately vs rs10455872 noncarriers. Also, for a 1 standard deviation higher lipoprotein(a) (= 310 mg/L), the hazard ratio for major bleeding in the brain and airways was 0.95 (95%CI: 0.91–1.00) observationally, 0.89 (0.80–0.98) causally based on LPA KIV-2 number of repeats, and 0.94 (0.87–1.02) causally based on LPA rs10455872. CONCLUSIONS High lipoprotein(a) concentrations were associated with lower risk of major bleeding in the brain and airways observationally and causally. This indicates that lipoprotein(a) may play a role in hemostasis and wound healing.

5131Unmet need for secondary prevention in individuals from the general population with increased lipoprotein(a): a contemporary population-based study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C M Madsen ◽  
P R Kamstrup ◽  
A Langsted ◽  
A Varbo ◽  
B G Nordestgaard
Keyword(s):  
High Risk ◽  
General Population ◽  
Secondary Prevention ◽  
Unmet Need ◽  
Incidence Rates ◽  
Adverse Cardiovascular Event ◽  
General Population Study ◽  
Lipoprotein A ◽  
Cardiovascular Outcome Trials ◽  
High Concentrations

Abstract Background There is strong evidence linking high lipoprotein(a) (Lp(a)) to development of incident cardiovascular disease (CVD), but it is not clear whether Lp(a) is associated with risk of recurrent CVD events in individuals from the general population with preexisting CVD. This is of importance as the first drugs specifically aimed at lowering Lp(a) are currently in development, and these would likely be used primarily in individuals with established CVD for secondary prevention of recurrent CVD events. Purpose We tested the hypothesis that high concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD. Methods From the Copenhagen General Population Study (CGPS) (2003–2015) of 58,527 individuals with measurements of Lp(a) at baseline, 2,527 aged 20–79 with a history of CVD were studied. The primary endpoint was major adverse cardiovascular event (MACE). We also studied 1,115 individuals with CVD at baseline from the Copenhagen City Heart Study (CCHS) (1991–1994) and the Copenhagen Ischemic Heart Disease Study (CIHDS) (1991–1993). Results During a median follow-up of 5 years (range: 0–13, 13,974 person-years), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1,000 person-years were 29 (95% CI: 25–34) for individuals with Lp(a) <10mg/dL (<18nmol/L), 35 (30–41) for 10–49mg/dL (18–104nmol/L), 42 (34–51) for 50–99mg/dL (105–213nmol/L), and 54 (42–70) for ≥100mg/dL (≥214nmol/L) (see Figure). Compared to individuals with Lp(a) <10mg/dL (<18nmol/L), the MACE incidence rate ratios were 1.21 (0.98–1.50) for 10–49mg/dL (18–104nmol/L), 1.43 (1.12–1.82) for 50–99mg/dL (105–213nmol/L), and 1.85 (1.38–2.49) for ≥100mg/dL (≥214nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS with MACE incidence rates per 1,000 person-years of 94 (95 CI: 84–106) for individuals with Lp(a) <10mg/dL (<18nmol/L), 115 (103–129) for 10–49mg/dL (18–104nmol/L), 134 (115–156) for 50–99mg/dL (105–213nmol/L), and 140 (116–169) for ≥100mg/dL (≥214nmol/L). Conclusion High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population with preexisting CVD. This points to a possible unmet need for secondary prevention in individuals with increased Lp(a), and such individuals could be a target group for upcoming randomized cardiovascular outcome trials. Acknowledgement/Funding The Novo Nordisk Foundation, Herlev and Gentofte Hospital, Chief Physician Johan Boserup and Lise Boserup's Fund

Plasma Concentrations of Magnesium and Risk of Dementia: A General Population Study of 102 648 Individuals

2021 ◽  
Author(s):  
Jesper Qvist Thomassen ◽  
Janne S Tolstrup ◽  
Børge G Nordestgaard ◽  
Anne Tybjærg-Hansen ◽  
Ruth Frikke-Schmidt
Keyword(s):  
Blood Pressure ◽  
High Risk ◽  
General Population ◽  
Systolic Blood Pressure ◽  
Population Study ◽  
Plasma Concentrations ◽  
Human Organism ◽  
General Population Study ◽  
Alzheimer Dementia ◽  
Plasma Magnesium

Abstract Background Low and high concentrations of plasma magnesium are associated with increased risk of future all-cause dementia; however, the underlying reasons remain elusive. The magnesium ion is an important electrolyte serving as a cofactor in many enzymatic processes in the human organism. Magnesium affects both neuronal and vascular functions. We investigated the associations of plasma concentrations of magnesium associate with common subtypes of dementia as Alzheimer dementia and non-Alzheimer dementia, and potential pathways by which magnesium may affect risk of dementia. Methods Plasma concentrations of magnesium were measured in 102 648 individuals from the Copenhagen General Population Study. Cox regression and natural effects mediation analyses evaluated associations with either Alzheimer dementia or non-Alzheimer dementia. Results Multifactorially adjusted hazard ratios for non-Alzheimer dementia were 1.50(95% confidence interval (CI):1.21–1.87) for the lowest and 1.34(1.07–1.69) for the highest vs the fourth quintile (reference) of plasma magnesium concentrations. Diabetes, cumulated smoking, stroke, and systolic blood pressure mediated 10.4%(3.1–22.8%), 6.8%(1.2–14.0%), 1.3%(0.1–3.6%), and 1.0%(0.2–2.6%), respectively, in the lowest quintile, whereas stroke mediated 3.2%(0.4–11.9%) in the highest quintile. No associations were observed for Alzheimer dementia. Conclusions Low and high plasma magnesium concentrations were associated with high risk of vascular-related non-Alzheimer dementia, with the lowest risk observed at a concentration of 2.07 mg/dL (0.85 mmol/L). No association was observed for Alzheimer dementia. Mediation analysis suggested that diabetes may be in the causal pathway between low plasma magnesium concentrations and high risk of non-Alzheimer dementia, while cumulated smoking, stroke, and systolic blood pressure played minor mediating roles.

Plasma adiponectin and risk of asthma: observational analysis, genetic Mendelian randomisation and meta-analysis

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217675
Author(s):  
Maria Booth Nielsen ◽  
Børge G Nordestgaard ◽  
Marianne Benn ◽  
Yunus Çolak
Keyword(s):  
General Population ◽  
Population Study ◽  
Genetic Variants ◽  
Meta Analysis ◽  
High Plasma ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
General Population Study ◽  
Plasma Adiponectin ◽  
The Uk

BackgroundAdiponectin, an adipocyte-secreted protein-hormone with inflammatory properties, has a potentially important role in the development and progression of asthma. Unravelling whether adiponectin is a causal risk factor for asthma is an important issue to clarify as adiponectin could be a potential novel drug target for the treatment of asthma.ObjectiveWe tested the hypothesis that plasma adiponectin is associated observationally and causally (using genetic variants as instrumental variables) with risk of asthma.MethodsIn the Copenhagen General Population Study, we did an observational analysis in 28 845 individuals (2278 asthma cases) with plasma adiponectin measurements, and a genetic one-sample Mendelian randomisation analysis in 94 868 individuals (7128 asthma cases) with 4 genetic variants. Furthermore, in the UK Biobank, we did a genetic two-sample Mendelian randomisation analysis in 462 933 individuals (53 598 asthma cases) with 12 genetic variants. Lastly, we meta-analysed the genetic findings.ResultsWhile a 1 unit log-transformed higher plasma adiponectin in the Copenhagen General Population Study was associated with an observational OR of 1.65 (95% CI 1.29 to 2.08) for asthma, the corresponding genetic causal OR was 1.03 (95% CI 0.75 to 1.42). The genetic causal OR for asthma in the UK Biobank was 1.00 (95% CI 0.99 to 1.00). Lastly, genetic meta-analysis confirmed lack of association between genetically high plasma adiponectin and causal OR for asthma.ConclusionObservationally, high plasma adiponectin is associated with increased risk of asthma; however, genetic evidence could not support a causal association between plasma adiponectin and asthma.

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

Thorax ◽  
2017 ◽  
Vol 73 (8) ◽  
pp. 748-757 ◽  
Author(s):  
Camilla J Kobylecki ◽  
Signe Vedel-Krogh ◽  
Shoaib Afzal ◽  
Sune F Nielsen ◽  
Børge G Nordestgaard
Keyword(s):  
Lung Function ◽  
General Population ◽  
Respiratory Symptoms ◽  
High Plasma ◽  
Mendelian Randomisation ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
General Population Study ◽  
Plasma Urate ◽  
Genetically Determined

BackgroundUrate 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.MethodsWe 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.ResultsIn the two studies combined, multivariable-adjusted 100 µmol/L higher plasma urate was associated with −1.54% (95% CI −1.67 to −1.40) lower FEV1 % predicted and −1.57% (95% CI −1.69 to −1.44) lower FVC % predicted observationally; the corresponding estimates for genetically determined 100 µmol/L higher plasma urate were −0.46% (95% CI −1.17 to 0.25) and −0.40% (95% CI −1.03 to 0.23). High plasma urate was also associated with higher risk of respiratory symptoms; however, genetically determined high plasma urate was not associated with respiratory symptoms. Finally, we identified 14 151 individuals with COPD and found ORs of 1.08 (95% CI 1.06 to 1.11) for COPD observationally and 1.01 (95% CI 0.88 to 1.15) genetically per 100 µmol/L higher plasma urate.ConclusionHigh 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.

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