Anne Tybjaerg-Hansen

Frederiksberg Hospital, Фредериксберг, Capital Region, Denmark

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Publications (356)3506.9 Total impact


  • No preview · Article · Feb 2016 · The Journal of Clinical Endocrinology and Metabolism
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    Stefan Stender · Anne Tybjærg-Hansen
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    ABSTRACT: Purpose of review: 'Genetic proxies' are increasingly being used to predict the effects of drugs. We present an up-to-date overview of the use of human genetics to predict effects and adverse effects of lipid-targeting drugs. Recent findings: LDL cholesterol lowering variants in HMG-Coenzyme A reductase and Niemann-Pick C1-like protein 1, the targets for statins and ezetimibe, protect against ischemic heart disease (IHD). However, HMG-Coenzyme A reductase and Niemann-Pick C1-Like Protein 1-variants also increase the risk of type 2 diabetes and gallstone disease, respectively. Mutations in proprotein convertase subtilisin kexin 9 (PCSK9), apolipoprotein B, and microsomal triglyceride transfer protein cause low LDL cholesterol and protect against IHD. In addition, mutations in apolipoprotein B and microsomal triglyceride transfer protein cause hepatic steatosis, in concordance with drugs that inhibit these targets. Both mutations in PCSK9 and PCSK9-inhibition seem without adverse effects. Mutations in APOC3 cause low triglycerides and protect against IHD, and recent pharmacological APOC3-inhibition reported major reductions in plasma triglycerides. Human genetics support that low lipoprotein(a) protects against IHD, without adverse effects, and the first trial of lipoprotein(a) inhibition reduced lipoprotein(a) up to 78%. Summary: Recent genetic studies have confirmed the efficacy of statins and ezetimibe in protecting against IHD. Results from human genetics support that several lipid-lowering drugs currently under development are likely to prove efficacious in protecting against IHD, without major adverse effects.
    Full-text · Article · Feb 2016 · Current Opinion in Lipidology
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    ABSTRACT: Data on correlations of plasma apoE with levels of lipids and lipoproteins stratified by APOE genotypes as well as data exploring the association between plasma levels of apoE and risk of ischemic heart disease (IHD) are wanted.
    No preview · Article · Feb 2016
  • Jeppe Zacho · Thomas Benfield · Anne Tybjærg-Hansen · Børge G Nordestgaard
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    ABSTRACT: Background: The acute-phase reactant C-reactive protein (CRP) increases rapidly during an infection. We tested the hypothesis that chronic low-level increases in CRP are associated with an increased risk of infectious disease. Methods: We studied 9660 individuals from a prospective general population cohort, including 3592 in whom infectious disease developed, and another 60 896 individuals from a cross-sectional general population study, of whom 13 332 developed infectious disease; 55% were women, and the mean age was 57 years. Hospital diagnoses of infections in 1977-2010 were based on International Classification of Diseases-coded discharge records from the national Danish Patient Registry. We measured CRP concentrations and conducted genotyping for 4 CRP polymorphisms that increase CRP. Individuals with CRP >10 mg/L were excluded because of possible ongoing infection at the time of testing. Results: Individuals with CRP >3 mg/L had 1.2 and 1.7 times increased risk of infectious disease, in the prospective general population cohort and the cross-sectional general population study, respectively, compared with individuals with CRP <1 mg/L. In the combined populations, individuals in the highest CRP tertile (compared with the lowest) had an increased risk of bacterial diseases (hazard ratio 1.7, 95% CI 1.6-1.8), but not viral, mycosis, and parasitic diseases. The increased risk was mainly carried by pneumonia, sepsis, and particularly gram-negative infections. None of the genotype combinations examined conferred an increased risk of infectious disease. Conclusions: Chronic low-level CRP increases were associated with increased risk of bacterial infections, gram-negative infections in particular. Genotypes associated with increases in CRP were not associated with increased risk of infection.
    No preview · Article · Dec 2015 · Clinical Chemistry
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    ABSTRACT: Background and aims: Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population. Methods: We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population. Results: Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04-1.27) for IHD and 1.16 (1.00-1.36) for MI in men, and 0.94 (0.84-1.05) and 1.04 (0.85-1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in ε33 carriers were 1.18 (1.03-1.36) for IHD and 1.21 (0.98-1.49) for MI in men, and 0.91 (0.78-1.06) and 0.93 (0.71-1.21) in women. Thus, the present associations were independent of APOE genotype. Conclusion: These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations.
    No preview · Article · Dec 2015 · Atherosclerosis
  • Mette Christoffersen · Anne Tybjærg-Hansen
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    ABSTRACT: Association of common aging signs (i.e. male pattern baldness, hair graying, and facial wrinkles) as well as other age-related appearance factors (i.e. arcus corneae, xanthelasmata, and earlobe crease) with increased risk of ischemic heart disease was initially described in anecdotal reports from clinicians observing trends in the physical appearance of patients with ischemic heart disease. Following these early observations numerous epidemiological studies have reported these associations. Since the prevalences of both visible aging signs and ischemic heart disease have a strong correlation with increasing age, it has been extensively debated whether the observed associations could be entirely explained by a common association with age. Furthermore, the etiologies of the visible aging signs are rarely fully understood, and pathophysiological explanations for these associations remain controversial, and are mostly speculative. As a consequence of inconsistent findings and lack of mechanistic explanations for the observed associations with ischemic heart disease, consensus on the clinical importance of these visible aging signs has been lacking. The aim of this review is for each of the visible aging signs to (i) review the etiology, (ii) to discuss the current epidemiological evidence for an association with risk of ischemic heart disease, and (iii) to present possible pathophysiological explanations for these associations. Finally this review discusses the potential clinical implications of these findings.
    No preview · Article · Nov 2015 · Ageing research reviews
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    ABSTRACT: Context and objective: Whether endogenous sex hormones are associated with ischemic stroke(IS) is unclear. We tested the hypothesis that extreme concentrations of endogenous sex hormones are associated with risk of IS in the general population. Design, setting, and participants: Adult men(n=4,615) and women(n=4,724) with measurements of endogenous sex hormones during the 1981-83 examination of the Copenhagen City Heart Study, Denmark, were followed for up to 29 years for incident IS, with no loss to follow-up. Mediation analyses assessed whether risk of IS was mediated through potential mediators. Present and previous findings were summarized in meta-analyses. Main outcome measures: Plasma total testosterone and total estradiol were measured by competitive immunoassays. Diagnosis of IS was ascertained from the national Danish Patient Registry and the national Danish Causes of Death Registry and verified by experienced neurologists. Results: During follow-up, 524 men and 563 women developed IS. Men with testosterone concentrations ≤10th percentile compared to the 11-90th percentiles had a hazard ratio for IS of 1.34(95% confidence interval: 1.05-1.72); 21% of this risk was mediated by body mass index(p=0.002) and 14% by hypertension(p=0.02). In accordance with this, the corresponding hazard ratio was 1.46(1.09-1.95) in overweight/obese and hypertensive men. The corresponding hazard ratio in the meta-analysis was 1.43(1.21-1.70). Other extreme concentrations of testosterone or estradiol were not associated with risk of IS in men or women. Conclusions: Extreme low endogenous testosterone concentrations were associated with high risk of IS in men, a risk mediated in part by body mass index and hypertension. Whether or not low testosterone is a causal factor for IS or merely a biomarker of poor metabolic health is still not known.
    No preview · Article · Oct 2015 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
    Full-text · Article · Sep 2015 · Nature
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    ABSTRACT: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
    Full-text · Article · Sep 2015 · Nature
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    Full-text · Article · Sep 2015 · Nature Communications
  • Bo Kobberø Lauridsen · Stefan Stender · Anne Tybjærg-Hansen

    No preview · Article · Sep 2015 · Journal of the American College of Cardiology
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    ABSTRACT: A rare genetic variant in the desmosomal gene plakophilin-2 (PKP2) c.419C>T(p.(S140F)) has repeatedly been identified in patients with dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Whether this is a disease-causing variant remains highly controversial. We tested this hypothesis using three approaches. Initially, in a prospective study of 10 407 individuals from the general population, including 2688 who developed heart failure or arrhythmias during >14 years of follow-up, PKP2 c.419C>T was identified in 98 individuals (0.94%). PKP2 genotype was not associated with electrocardiographic or echocardiographic changes, or with plasma levels of probrain natriuretic peptide (all P≥0.05). In c.419C>T carriers versus non-carriers, multifactorially adjusted hazard ratios were 1.26 (95% confidence interval: 0.77–2.07) for heart failure, 1.40 (0.90–2.17) for arrhythmias, 1.15 (0.78–1.71) for end points combined, and 1.33 (0.98–1.80) for all-cause mortality. The cumulative survival as a function of age and PKP2 genotype was similar among carriers and non-carriers (P=0.14). Second, comparing 517 patients referred for genetic testing with 1918 matched controls, odds ratios as a function of c.419C>T genotype were 2.11 (0.50–8.99) for ARVC, 0.72 (0.16–3.28) for hypertrophic cardiomyopathy (HCM)/DCM, and 1.28 (0.46–3.54) for end points combined. Third, in in vitro studies cellular localization of plakophilin-2, plakoglobin, connexin-43, or N-cadherin were similar in cells transfected with wild-type or mutant plakophilin-2. In conclusion, combining epidemiological data, with data on patients referred for genetic testing for ARVC or HCM/DCM, and data from in vitro studies, PKP2 c.419C>T did not associate with heart failure, arrhythmias, or premature death, with ARVC or HCM/DCM, or with effects in vitro, suggesting that this is not a disease-causing variant.
    No preview · Article · Aug 2015 · European journal of human genetics: EJHG
  • L. Nordestgaard · A. Tybjærg-Hansen · B. Nordestgaard · R. Frikke-Schmidt

    No preview · Article · Jul 2015 · Atherosclerosis
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    ABSTRACT: The adenosine triphosphate-binding cassette transporter A1 (ABCA1) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways. We tested whether a loss-of-function mutation in ABCA1, N1800H, is associated with plasma levels of apoE and with risk of Alzheimer disease in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals. N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE (P = 1 × 10(-11)). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32-12.9) for Alzheimer disease, 2.46 (1.10-5.50) for cerebrovascular disease, and 8.28 (2.03-33.7) for the hemorrhagic stroke subtype. A loss-of-function mutation in ABCA1, present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of Alzheimer disease and cerebrovascular disease in the general population. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    ABSTRACT: Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD). Globally, one baby is born with FH every minute. If diagnosed and treated early in childhood, individuals with FH can have normal life expectancy. This consensus paper aims to improve awareness of the need for early detection and management of FH children. Familial hypercholesterolaemia is diagnosed either on phenotypic criteria, i.e. an elevated low-density lipoprotein cholesterol (LDL-C) level plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis, or positive genetic testing. Childhood is the optimal period for discrimination between FH and non-FH using LDL-C screening. An LDL-C ≥5 mmol/L (190 mg/dL), or an LDL-C ≥4 mmol/L (160 mg/dL) with family history of premature CHD and/or high baseline cholesterol in one parent, make the phenotypic diagnosis. If a parent has a genetic defect, the LDL-C cut-off for the child is ≥3.5 mmol/L (130 mg/dL). We recommend cascade screening of families using a combined phenotypic and genotypic strategy. In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. A healthy lifestyle and statin treatment (from age 8 to 10 years) are the cornerstones of management of heterozygous FH. Target LDL-C is <3.5 mmol/L (130 mg/dL) if >10 years, or ideally 50% reduction from baseline if 8-10 years, especially with very high LDL-C, elevated lipoprotein(a), a family history of premature CHD or other cardiovascular risk factors, balanced against the long-term risk of treatment side effects. Identifying FH early and optimally lowering LDL-C over the lifespan reduces cumulative LDL-C burden and offers health and socioeconomic benefits. To drive policy change for timely detection and management, we call for further studies in the young. Increased awareness, early identification, and optimal treatment from childhood are critical to adding decades of healthy life for children and adolescents with FH. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
    Full-text · Article · May 2015 · European Heart Journal
  • Mette Christoffersen · Anne Tybjærg-Hansen
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    ABSTRACT: To summarize recent findings from genome-wide association studies (GWAS), whole-exome sequencing of patients with familial hypercholesterolemia and 'exome chip' studies pointing to novel genes in LDL metabolism. The genetic loci for ATP-binding cassette transporters G5 and G8, Niemann-Pick C1-Like protein 1, sortilin-1, ABO blood-group glycosyltransferases, myosin regulatory light chain-interacting protein and cholesterol 7α-hydroxylase have all consistently been associated with LDL cholesterol levels and/or coronary artery disease in GWAS. Whole-exome sequencing and 'exome chip' studies have additionally suggested several novel genes in LDL metabolism including insulin-induced gene 2, signal transducing adaptor family member 1, lysosomal acid lipase A, patatin-like phospholipase domain-containing protein 5 and transmembrane 6 superfamily member 2. Most of these findings still require independent replications and/or functional studies to confirm the exact role in LDL metabolism and the clinical implications for human health. GWAS, exome sequencing studies, and recently 'exome chip' studies have suggested several novel genes with effects on LDL cholesterol. Novel genes in LDL metabolism will improve our understanding of mechanisms in LDL metabolism, and may lead to the identification of new drug targets to reduce LDL cholesterol levels.
    No preview · Article · Apr 2015 · Current opinion in lipidology
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    ABSTRACT: Ezetimibe reduces plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1 (NPC1L1), the transporter responsible for cholesterol uptake from the intestine into enterocytes and from the bile into hepatocytes. We tested the hypothesis that genetic variation in NPC1L1, mimicking the effect of ezetimibe, was associated with reduced risk of ischaemic vascular disease (IVD) and with increased risk of symptomatic gallstone disease. We included 67 385 individuals from the general population. Of these, 5255 and 3886 individuals developed IVD or symptomatic gallstone disease, respectively, during follow-up from 1977 to 2013. We genotyped four common NPC1L1variants, previously associated with reduced LDL cholesterol levels, thus mimicking the effect of ezetimibe, and calculated a weighted genotype score. With increasing genotype score, LDL cholesterol decreased stepwise up to 3.5% (0.12 mmol/L) and total cholesterol up to 1.9% (0.11 mmol/L) (P-trend: 2 × 10(-12) and 2 × 10(-9)). The cumulative incidence by age of IVD decreased, while that of symptomatic gallstone disease increased as a function of increasing genotype score (P-trend: 0.005 and 0.01). Hazard ratios for genotype scores ≥5.0 vs. <2.0 were 0.82 (95% confidence interval: 0.70-0.95) for IVD and 1.22 (0.99-1.49) for gallstone disease (P-trend across genotype scores: 0.004 and 0.01). Genetic variation in NPC1L1 is associated with a reduction in risk of IVD, with a corresponding reduction in LDL cholesterol, but with a concomitant increased risk of gallstone disease. These data support the hypothesis that treatment with ezetimibe protects against IVD but raise the question whether long-term treatment increases the risk of gallstone disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    Full-text · Article · Apr 2015 · European Heart Journal
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    ABSTRACT: Background To investigate potential cardiovascular and other eff ects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of infl ammation.
    Full-text · Article · Mar 2015 · The Lancet Diabetes & Endocrinology
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    ABSTRACT: Objective: The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. It remains however unclear whether plasma levels of apoE confer additional risk. We tested this hypothesis. Methods: Using 75,708 participants from the general population, we tested whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype. Results: Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia increased from the highest to the lowest apoE tertile (p for trends:<1 × 10(-6) ). Multifactorially adjusted HRs for lowest versus highest tertile were 2.68 (95% confidence interval: 2.04-3.52) and 1.80 (1.52-2.13) for Alzheimer disease and all dementia, respectively. After further adjustment for ε2/ε3/ε4 APOE genotype, plasma apoE tertiles remained associated with Alzheimer disease (p for trend=0.007) and all dementia (p for trend=0.04). Plasma apoE tertiles did not interact with ε2/ε3/ε4 APOE genotype on risk of Alzheimer disease (p=0.53) or all dementia (p=0.79). In a subanalysis, the -219G>T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for ε2/ε3/ε4 APOE genotype (HR: 1.56 (1.05-2.30)). Interpretation: Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype. This is clinically relevant, because no plasma biomarkers currently are implemented. Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker. This article is protected by copyright. All rights reserved. © 2014 American Neurological Association.
    No preview · Article · Feb 2015 · Annals of Neurology
  • K Walter · JL Min · J Huang · L Crooks · Y Memari · S McCarthy · JRB Perry · C Xu · M Futema · D Lawson · [...] · M Traglia · A Tybjaerg-Hansen · CM van Duijn · EM van Leeuwen · A Varbo · P Whincup · G Zaza · WH Zhang · UK Consortium · U Consortium ·
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    ABSTRACT: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
    No preview · Article · Jan 2015 · Nature

Publication Stats

18k Citations
3,506.90 Total Impact Points

Institutions

  • 2014-2015
    • Frederiksberg Hospital
      Фредериксберг, Capital Region, Denmark
    • University of Pennsylvania
      • Institute for Translational Medicine and Therapeutics
      Philadelphia, Pennsylvania, United States
  • 1997-2015
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • Herlev Hospital
      • Department of Pathology
      Herlev, Capital Region, Denmark
    • University of Washington Seattle
      Seattle, Washington, United States
    • Rigshospitalet
      København, Capital Region, Denmark
    • National University (California)
      San Diego, California, United States
  • 2003-2014
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 1992-2013
    • Bispebjerg Hospital, Copenhagen University
      • Department of Cardiology
      København, Capital Region, Denmark
    • Oxford University Hospitals NHS Trust
      • Department of Haematology
      Oxford, England, United Kingdom
  • 2012
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1997-2012
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2002
    • Hillerød Hospital
      • Department of Cardiology
      Hillerød, Capital Region, Denmark
  • 1998
    • Glostrup Hospital
      • Department of Clinical Biochemistry
      Glostrup, Capital Region, Denmark
  • 1991
    • Copenhagen University Hospital Hvidovre
      Hvidovre, Capital Region, Denmark