Publications by authors named "Anke H Maitland-van der Zee"

115 Publications

Inflammation and its associations with aortic stiffness, coronary artery disease and peripheral artery disease in different ethnic groups: The HELIUS Study.

EClinicalMedicine 2021 Aug 7;38:101012. Epub 2021 Jul 7.

Department of Internal and Vascular Medicine, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Amsterdam, the Netherlands.

Background: evidence shows important ethnic differences in vascular dysfunction rates; however, the mechanisms driving these differences remain unclear. One potential factor is the ethnic differences in the role of inflammation in vascular injury. We tested the hypothesis that low-grade inflammation is unequally associated with vascular dysfunction in different ethnic groups.

Methods: we included 5698 participants (similar-sized Dutch, African Surinamese, South-Asian Surinamese, Ghanaians, Turkish, and Moroccans) of the HELIUS study (the Netherlands) conducted between 2011 and 2015. Logistic regression was used to examine the associations of Z-score inflammatory biomarker concentration (high sensitivity C-reactive protein [hs-CRP], fibrinogen, and d-dimer) with vascular dysfunction (aortic stiffness, coronary artery disease [CAD], and peripheral artery disease [PAD]), with adjustments for age, sex, smoking (pack-years), BMI, hypertension, HbA1c, total cholesterol, and statin use.

Findings: in the fully adjusted models, higher Z-score hs-CRP was positively associated with CAD in Dutch [OR 1·63, (95% CI 1·21-2·18)] and PAD in South Asians [1·25(1·03-1·53)], respectively. Higher Z-score fibrinogen was positively associated with CAD in African Surinamese [1·28(1·03-1·59)] while higher Z-score d-dimer was positively associated with PAD in Moroccans [1·39(1·01-1·93)]. Higher Z-score hs-CRP [0·71(0·54-0·94)] and fibrinogen [0·75(0·58-0·97)] concentrations were negatively associated with PAD in African Surinamese.

Interpretation: our study shows that inflammatory biomarkers are unequally associated with vascular dysfunction in different ethnic groups. These observations provide opportunities for future studies aimed at assessing the predictive roles of inflammation on vascular disease in different ethnic groups.
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http://dx.doi.org/10.1016/j.eclinm.2021.101012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271115PMC
August 2021

ADRB2 haplotypes and asthma exacerbations in children and young adults: An individual participant data meta-analysis.

Clin Exp Allergy 2021 Jun 15. Epub 2021 Jun 15.

Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: The polymorphism Arg16 in β -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27.

Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA.

Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects.

Results: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I  = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I  = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I  = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β -agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686).

Conclusion And Clinical Relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.
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http://dx.doi.org/10.1111/cea.13965DOI Listing
June 2021

A System Pharmacology Multi-Omics Approach toward Uncontrolled Pediatric Asthma.

J Pers Med 2021 May 28;11(6). Epub 2021 May 28.

Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

There is a clinical need to identify children with poor asthma control as early as possible, to optimize treatment and/or to find therapeutic alternatives. Here, we present the "Systems Pharmacology Approach to Uncontrolled Pediatric Asthma" (SysPharmPediA) study, which aims to establish a pediatric cohort of moderate-to-severe uncontrolled and controlled patients with asthma, to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach. In this multicenter observational case-control study, moderate-to-severe asthmatic children (age; 6-17 years) were included from four European countries (Netherlands, Germany, Spain, and Slovenia). Subjects were classified based on asthma control and number of exacerbations. Demographics, current and past patient/family history, and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics, and metabolomics were evaluated from multiple samples. In all, 145 children were included in this cohort, 91 with uncontrolled (median age = 12 years, 43% females) and 54 with controlled asthma (median age = 11.7 years, 37% females). The two groups did not show statistically significant differences in age, sex, and body mass index z-score distribution. Comprehensive information and diverse noninvasive biosampling procedures for various omics analyses will provide the opportunity to delineate underlying pathophysiological mechanisms of moderate-to-severe uncontrolled pediatric asthma. This eventually might reveal novel biomarkers, which could potentially be used for noninvasive personalized diagnostics and/or treatment.
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http://dx.doi.org/10.3390/jpm11060484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227234PMC
May 2021

Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients.

J Cyst Fibros 2021 May 17. Epub 2021 May 17.

Department Respiratory Medicine, Amsterdam University Medical Centres - loc. AMC, University of Amsterdam, Amsterdam, Netherlands; Department Paediatric Respiratory Medicine and Allergy, Emma Children's Hospital, Amsterdam University Medical Centres, Amsterdam, the Netherlands. Electronic address:

Background: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively.

Methods: This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture.

Results: 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71-1.0) and 0.87 (CI 0.72-1.0) for adults and children, respectively.

Conclusions: Targeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values.
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http://dx.doi.org/10.1016/j.jcf.2021.04.015DOI Listing
May 2021

The Impact of Short-Term Exposure to Air Pollution on the Exhaled Breath of Healthy Adults.

Sensors (Basel) 2021 Apr 4;21(7). Epub 2021 Apr 4.

Amsterdam UMC, Department of Respiratory Medicine, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Environmental factors, such as air pollution, can affect the composition of exhaled breath, and should be well understood before biomarkers in exhaled breath can be used in clinical practice. Our objective was to investigate whether short-term exposures to air pollution can be detected in the exhaled breath profile of healthy adults. In this study, 20 healthy young adults were exposed 2-4 times to the ambient air near a major airport and two highways. Before and after each 5 h exposure, exhaled breath was analyzed using an electronic nose (eNose) consisting of seven different cross-reactive metal-oxide sensors. The discrimination between pre and post-exposure was investigated with multilevel partial least square discriminant analysis (PLSDA), followed by linear discriminant and receiver operating characteristic (ROC) analysis, for all data (71 visits), and for a training (51 visits) and validation set (20 visits). Using all eNose measurements and the training set, discrimination between pre and post-exposure resulted in an area under the ROC curve of 0.83 (95% CI = 0.76-0.89) and 0.84 (95% CI = 0.75-0.92), whereas it decreased to 0.66 (95% CI = 0.48-0.84) in the validation set. Short-term exposure to high levels of air pollution potentially influences the exhaled breath profiles of healthy adults, however, the effects may be minimal for regular daily exposures.
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http://dx.doi.org/10.3390/s21072518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038449PMC
April 2021

SHARP: enabling generation of real-world evidence on a pan-European scale to improve the lives of individuals with severe asthma.

ERJ Open Res 2021 Apr 19;7(2). Epub 2021 Apr 19.

Respiratory Research Unit, Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark.

Real-world evidence is important to help unravel unanswered problems in severe asthma and is valuable to better understand the patient experience and common clinical practice. The Severe Heterogeneous Asthma Registry, Patient-centred (SHARP) Clinical Research Collaboration is created as a network of national registries and severe asthma centres that work together to perform registry based real-world research and clinical studies on a pan-European scale. Such collaboration requires a new, innovative design to overcome the many issues that arise with large-scale data collection across national borders. SHARP has developed a platform that offers a federated analysis approach where national registry data are transformed and integrated into a common data model (CDM). The CDM then allows a local analysis of de-identified patient data and subsequent aggregate (meta-)analysis. To facilitate an easily accessible way to set up new registries, SHARP enables new registries to take part in a central database, based on already proven technology. Next to being economical, this linkage ensures data from different SHARP central members to be comparable. Technological advancements lead to an ever-expanding rate of patient data that will be collected; with the collective effort of the pan-European severe asthma research community SHARP hopes to ensure that they are well equipped to enter a new era of medical research, with the ultimate goal to positively impact the lives of patients with severe asthma.
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http://dx.doi.org/10.1183/23120541.00064-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053907PMC
April 2021

Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients.

ERJ Open Res 2021 Apr 19;7(2). Epub 2021 Apr 19.

Dept of Respiratory Medicine, Amsterdam UMC - Location AMC, University of Amsterdam, Amsterdam, the Netherlands.

Rationale: Targeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes may occur in the microbiome, which is adapted to CF lungs.

Objectives: To investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract.

Methods: This was a single-centre longitudinal observational cohort study in adult CF patients with a homozygous Phe508del mutation. Lung function measurements and microbial cultures of sputum were performed as part of routine care. An oral and nasal wash, and a breath sample, were collected before and every 3 months after starting therapy, for up to 12 months.

Results: Twenty patients were included in this study. Amplicon 16S RNA and metagenomics sequencing revealed that was most abundant in sputum and seemed to decrease after 6 months of treatment, although this did not reach statistical significance after correction for multiple testing. Two types of untargeted metabolomics analyses in sputum showed a change in metabolic composition between 3 and 9 months that almost returned to baseline levels after 12 months of treatment. The volatile metabolic composition of breath was significantly different after 3 months and remained different from baseline until 12 months follow-up.

Conclusions: After starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in the lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of .
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http://dx.doi.org/10.1183/23120541.00731-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053817PMC
April 2021

Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma.

J Allergy Clin Immunol 2021 Apr 20. Epub 2021 Apr 20.

Clinical and Experimental Sciences and Human Development in Health, University of Southampton Faculty of Medicine, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight, United Kingdom.

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.

Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T2, and T17/T22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T22/IL-22 pathways.

Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
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http://dx.doi.org/10.1016/j.jaci.2021.04.010DOI Listing
April 2021

Treating severe asthma: Targeting the IL-5 pathway.

Clin Exp Allergy 2021 Aug 21;51(8):992-1005. Epub 2021 May 21.

Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)-4, IL-5 and IL-13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL-5R and IL-5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late-onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non-response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL-5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non-response.
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http://dx.doi.org/10.1111/cea.13885DOI Listing
August 2021

The Influence of Smoking Status on Exhaled Breath Profiles in Asthma and COPD Patients.

Molecules 2021 Mar 4;26(5). Epub 2021 Mar 4.

Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Breath analysis using eNose technology can be used to discriminate between asthma and COPD patients, but it remains unclear whether results are influenced by smoking status. We aim to study whether eNose can discriminate between ever- vs. never-smokers and smoking <24 vs. >24 h before the exhaled breath, and if smoking can be considered a confounder that influences eNose results. We performed a cross-sectional analysis in adults with asthma or chronic obstructive pulmonary disease (COPD), and healthy controls. Ever-smokers were defined as patients with current or past smoking habits. eNose measurements were performed by using the SpiroNose. The principal component (PC) described the eNose signals, and linear discriminant analysis determined if PCs classified ever-smokers vs. never-smokers and smoking <24 vs. >24 h. The area under the receiver-operator characteristic curve (AUC) assessed the accuracy of the models. We selected 593 ever-smokers (167 smoked <24 h before measurement) and 303 never-smokers and measured the exhaled breath profiles of discriminated ever- and never-smokers (AUC: 0.74; 95% CI: 0.66-0.81), and no cigarette consumption <24h (AUC 0.54, 95% CI: 0.43-0.65). In healthy controls, the eNose did not discriminate between ever or never-smokers (AUC 0.54; 95% CI: 0.49-0.60) and recent cigarette consumption (AUC 0.60; 95% CI: 0.50-0.69). The eNose could distinguish between ever and never-smokers in asthma and COPD patients, but not recent smokers. Recent smoking is not a confounding factor of eNose breath profiles.
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http://dx.doi.org/10.3390/molecules26051357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961431PMC
March 2021

Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis.

Crit Rev Oncol Hematol 2021 May 29;161:103312. Epub 2021 Mar 29.

BC Children's Hospital Research Institute, Vancouver, BC, Canada; Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; Pharmaceutical Outcomes Programme, BC Children's Hospital, Vancouver, BC, Canada. Electronic address:

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95 %CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16-3.73], FDR-corrected p-value 0.042).
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http://dx.doi.org/10.1016/j.critrevonc.2021.103312DOI Listing
May 2021

Higher prescription of antidepressants and/or anxiolytics among chronic obstructive pulmonary disease patients.

Ther Adv Respir Dis 2021 Jan-Dec;15:1753466620961696

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, 3508 TC, The Netherlands.

Background: Chronic obstructive pulmonary disease (COPD) is often accompanied by psychiatric problems, such as depression and anxiety, affecting both treatment outcomes and mortality. Evidence for the number of COPD patients using medication for these disorders is sparse. In this study, chronic antidepressant (ATD) and anxiolytic (ANX) drug use - to identify depression and anxiety - among COPD patients was compared with subjects with or without other chronic diseases.

Methods: The NControl database containing prescription data of 800 pharmacies including 7 million individuals in The Netherlands was used. Patients of age 55+ years who received frequent prescriptions - at least two/year in 5 out of 6 years - for COPD medication, dermatological drugs, disease-modifying antirheumatic drugs (DMARDs), statins and oral glucose-lowering medication were analyzed for concomitant chronic use of ATDs and ANXs between 1 January 2013 and 1 January 2019. All other subjects aged 55+ years were included as a control group (control group 1). This group was further stratified into a group of subjects that received frequent prescriptions of any kind (control group 2).

Results: 15.2% of the patients that receive COPD treatment ( = 96,319), 15.3% of subjects that are treated for dermatological problems ( = 62,865), 13.2% of subjects that receive DMARDs ( = 7900), 11.6% of statins users ( = 422,376) and 11.4% of oral glucose-lowering medication users ( = 165,975) are also chronically treated for depression or anxiety, compared with 2.6% (control group 1;  = 3,290,608) and 11.4% (control group 2;  = 757,947). In general, female and 75+ years aged subjects showed a higher risk for using ATDs and ANXs chronically. In the COPD and the dermatological patient group the risk was the highest compared with the other patient groups.

Conclusions: The rates of chronic ATD and ANX use and the risk of having depression and/or anxiety are especially high in COPD patients, indicating that psychiatric problems are more common in COPD than in most other chronic diseases. In general, age and gender strongly influence the risk of chronically using ATDs and ANXs.
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http://dx.doi.org/10.1177/1753466620961696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093612PMC
March 2021

Pharmacoepidemiology: A time for a new multidisciplinary approach to precision medicine.

Pharmacoepidemiol Drug Saf 2021 Aug 7;30(8):985-992. Epub 2021 Apr 7.

School of Medicine, University of Missouri, Columbia, Missouri, USA.

The advent of the genomic age has created a rapid increase in complexity for the development and selection of drug treatments. A key component of precision medicine is the use of genetic information to improve therapeutic effectiveness of drugs and prevent potential adverse drug reactions. Pharmacoepidemiology, as a field, uses observational methods to evaluate the safety and effectiveness of drug treatments in populations. Pharmacoepidemiology by virtue of its focus, tradition, and research orientation can provide appropriate study designs and analysis methods for precision medicine. The objective of this manuscript is to demonstrate how pharmacoepidemiology can impact and shape precision medicine and serve as a reference for pharmacoepidemiologists interested in contributing to the science of precision medicine. This paper depicts the state of the science with respect to the need for pharmacoepidemiology and pharmacoepidemiological methods, tools and approaches for precision medicine; the need for and how pharmacoepidemiologists use their skills to engage with the precision medicine community; and recommendations for moving the science of precision medicine pharmacoepidemiology forward. We propose a new integrated multidisciplinary approach dedicated to the emerging science of precision medicine pharmacoepidemiology.
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http://dx.doi.org/10.1002/pds.5226DOI Listing
August 2021

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

Pediatr Allergy Immunol 2021 Aug 29;32(6):1197-1207. Epub 2021 Mar 29.

Department of Respiratory Disease, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium.

Methods: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma.

Results: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10 ) associated with exacerbations despite LABA use.

Conclusion: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.
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http://dx.doi.org/10.1111/pai.13494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328929PMC
August 2021

Associations between macrovascular and renal microvascular dysfunction in type 2 diabetes and non-diabetes: the HELIUS study.

Microvasc Res 2021 07 9;136:104162. Epub 2021 Mar 9.

Department of Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Background: Although the associations between measures of macrovascular and microvascular dysfunctions are well characterized in diabetes, there is limited data on these associations in individuals without diabetes. We compared the associations between macrovascular dysfunction and renal microvascular dysfunction in individuals with type 2 diabetes (T2D) and without diabetes.

Methods: Cross-sectional analyses of baseline data from the multiethnic Healthy Life in an Urban Setting (HELIUS) study (Amsterdam, the Netherlands), including 986 participants with T2D and 7680 participants without diabetes were done. Logistic regression analyses were used to examine the associations between macrovascular dysfunction [aortic stiffness, coronary artery disease (CAD), peripheral artery disease (PAD), and stroke] and renal microvascular dysfunction [albuminuria] with adjustments for age, sex, ethnicity, waist-to-hip ratio, systolic blood pressure, LDL-cholesterol, and smoking (and HbA1c and diabetes duration for the T2D group).

Results: In the fully adjusted models, aortic stiffness was associated with albuminuria in individuals with T2D [OR 2.55; 95% CI,1.30-4.98], but not without diabetes [0.96; 0.63-1.45]; stroke was associated with albuminuria in T2D [2.40;1.10-5.25], but not in non-diabetes [1.39;0.83-2.33]. In age-sex adjusted models, CAD was associated with albuminuria in T2D [1.65;1.09-2.50] and in non-diabetes [1.56;1.13-2.15]; the associations were no longer significant in the fully adjusted model. There were no associations between PAD and albuminuria in T2D and non-diabetes.

Conclusions: Our study shows important differences in the associations between measures of macrovascular and renal microvascular dysfunction in T2D and non-diabetes. These findings provide opportunities for future research aimed at prevention and treatment strategies for individuals with vascular dysfunction.
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http://dx.doi.org/10.1016/j.mvr.2021.104162DOI Listing
July 2021

Increased day-to-day fluctuations in exhaled breath profiles after a rhinovirus challenge in asthma.

Allergy 2021 Aug 27;76(8):2488-2499. Epub 2021 Mar 27.

Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Early detection/prediction of flare-ups in asthma, commonly triggered by viruses, would enable timely treatment. Previous studies on exhaled breath analysis by electronic nose (eNose) technology could discriminate between stable and unstable episodes of asthma, using single/few time-points. To investigate its monitoring properties during these episodes, we examined day-to-day fluctuations in exhaled breath profiles, before and after a rhinovirus-16 (RV16) challenge, in healthy and asthmatic adults.

Methods: In this proof-of-concept study, 12 atopic asthmatic and 12 non-atopic healthy adults were prospectively followed thrice weekly, 60 days before, and 30 days after a RV16 challenge. Exhaled breath profiles were detected using an eNose, consisting of 7 different sensors. Per sensor, individual means were calculated using pre-challenge visits. Absolute deviations (|%|) from this baseline were derived for all visits. Within-group comparisons were tested with Mann-Whitney U tests and receiver operating characteristic (ROC) analysis. Finally, Spearman's correlations between the total change in eNose deviations and fractional exhaled nitric oxide (FeNO), cold-like symptoms, and pro-inflammatory cytokines were examined.

Results: Both groups had significantly increased eNose fluctuations post-challenge, which in asthma started 1 day post-challenge, before the onset of symptoms. Discrimination between pre- and post-challenge reached an area under the ROC curve of 0.82 (95% CI = 0.65-0.99) in healthy and 0.97 (95% CI = 0.91-1.00) in asthmatic adults. The total change in eNose deviations moderately correlated with IL-8 and TNFα (ρ ≈ .50-0.60) in asthmatics.

Conclusion: Electronic nose fluctuations rapidly increase after a RV16 challenge, with distinct differences between healthy and asthmatic adults, suggesting that this technology could be useful in monitoring virus-driven unstable episodes in asthma.
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http://dx.doi.org/10.1111/all.14811DOI Listing
August 2021

Identification of recent exacerbations in COPD patients by electronic nose.

ERJ Open Res 2020 Oct 21;6(4). Epub 2020 Dec 21.

Amsterdam UMC, University of Amsterdam, Dept of Respiratory Medicine, Amsterdam, The Netherlands.

Molecular profiling of exhaled breath by electronic nose (eNose) might be suitable as a noninvasive tool that can help in monitoring of clinically unstable COPD patients. However, supporting data are still lacking. Therefore, as a first step, this study aimed to determine the accuracy of exhaled breath analysis by eNose to identify COPD patients who recently exacerbated, defined as an exacerbation in the previous 3 months. Data for this exploratory, cross-sectional study were extracted from the multicentre BreathCloud cohort. Patients with a physician-reported diagnosis of COPD (n=364) on maintenance treatment were included in the analysis. Exacerbations were defined as a worsening of respiratory symptoms requiring treatment with oral corticosteroids, antibiotics or both. Data analysis involved eNose signal processing, ambient air correction and statistics based on principal component (PC) analysis followed by linear discriminant analysis (LDA). Before analysis, patients were randomly divided into a training (n=254) and validation (n=110) set. In the training set, LDA based on PCs 1-4 discriminated between patients with a recent exacerbation or no exacerbation with high accuracy (receiver operating characteristic (ROC)-area under the curve (AUC)=0.98, 95% CI 0.97-1.00). This high accuracy was confirmed in the validation set (AUC=0.98, 95% CI 0.94-1.00). Smoking, health status score, use of inhaled corticosteroids or vital capacity did not influence these results. Exhaled breath analysis by eNose can discriminate with high accuracy between COPD patients who experienced an exacerbation within 3 months prior to measurement and those who did not. This suggests that COPD patients who recently exacerbated have their own exhaled molecular fingerprint that could be valuable for monitoring purposes.
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http://dx.doi.org/10.1183/23120541.00307-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792783PMC
October 2020

Nonadherence to inhaled corticosteroids: A characteristic of the pediatric obese-asthma phenotype?

Pediatr Pulmonol 2021 May 12;56(5):948-956. Epub 2021 Jan 12.

Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Background: Children with excess weight and asthma tend to respond less well to inhaled corticosteroids (ICS) than children with normal weight, potentially resulting in nonadherence to ICS.

Objectives: To assess whether excess weight (body mass index ≥85th percentile) was associated with general, unintentional, and intentional nonadherence to ICS in children with asthma.

Methods: We analyzed data from 566 children aged 4-13 years with asthma, who used ICS as maintenance therapy, from the cross-sectional Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects study. General nonadherence was measured objectively with the proportion of days covered (<50%) and subjectively with the parent-reported Medication Adherence Rating Scale (MARS <21) reflecting parent-reported nonadherent behavior. Unintentional and intentional nonadherence were defined as forgetting to take medication and deliberately changing or skipping doses, respectively, from specific items of the MARS. We performed logistic regression analyses, stratifying estimates by asthma severity and age group.

Results: Excess weight was associated with a trend towards increased odds of parent-reported nonadherent behavior (odds ratio [OR]: 1.54; 95% confidence interval [CI]: 0.84-2.81) and objectively measured general nonadherence, but only in moderate-to-severe asthma (OR: 1.71; 95% CI: 0.84-3.48). The odds of intentional, but not unintentional, nonadherence seemed to be greater in children with excess weight than normal weight (OR: 1.94; 95% CI: 0.94-4.01), and the association appeared to be stronger in younger (OR: 2.17; 95% CI 1.00-4.73) versus older children (OR: 1.18; 95% CI: 0.36-3.94).

Conclusions: Excess weight was associated with general nonadherence to ICS, but only in children with moderate-to-severe asthma, and nonadherent behavior, which seemed to be intentional.
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http://dx.doi.org/10.1002/ppul.25253DOI Listing
May 2021

Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.

Eur Respir J 2021 05 13;57(5). Epub 2021 May 13.

Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Maribor, Slovenia.

Rationale: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.

Methods: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.

Results: 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10). Of those, one variant at the locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.

Conclusions: The intergenic region of and was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
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http://dx.doi.org/10.1183/13993003.03388-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122045PMC
May 2021

Precision Medicine in Neonates: Future Perspectives for the Lung.

Front Pediatr 2020 30;8:586061. Epub 2020 Oct 30.

Department of Neonatology, Amsterdam University Medical Centers, VU University Medical Center, Emma Children's Hospital, University of Amsterdam, Amsterdam, Netherlands.

Bronchopulmonary dysplasia (BPD) is the most common complication of pre-term birth with long lasting sequelae. Since its first description more than 50 years ago, many large randomized controlled trials have been conducted, aiming to improve evidence-based knowledge on the optimal strategies to prevent and treat BPD. However, most of these intervention studies have been performed on a population level without regard for the variation in clinical and biological diversity (e.g., gestational age, ethnicity, gender, or disease progression) between patients that is driven by the complex interaction of genetic pre-disposition and environmental exposures. Nevertheless, clinicians provide daily care such as lung protective interventions on an individual basis every day despite the fact that research supporting individualized or precision medicine for monitoring or treating pre-term lungs is immature. This narrative review summarizes four potential developments in pulmonary research that might facilitate the process of individualizing lung protective interventions to prevent development of BPD. Electrical impedance tomography and electromyography of the diaphragm are bedside monitoring tools to assess regional changes in lung volume and ventilation and spontaneous breathing effort, respectively. These non-invasive tools allow a more individualized optimization of invasive and non-invasive respiratory support. Investigation of the genomic variation in caffeine metabolism in pre-term infants can be used to optimize and individualize caffeine dosing regimens. Finally, volatile organic compound analysis in exhaled breath might accurately predict BPD at an early stage of the disease, enabling clinicians to initiate preventive strategies for BPD on an individual basis. Before these suggested diagnostic or monitoring tools can be implemented in daily practice and improve individualized patient care, future research should address and overcome their technical difficulties, perform extensive external validation and show their additional value in preventing BPD.
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http://dx.doi.org/10.3389/fped.2020.586061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673376PMC
October 2020

Impact of a Variant on Clinical Disease Phenotype in Homozygous Patients With Cystic Fibrosis.

Front Genet 2020 28;11:570403. Epub 2020 Oct 28.

Abt. Allgemeine Pädiatrie, Zentrum für Kinderheilkunde des Universitätsklinikums Bonn, Bonn, Germany.

Background: Lung disease phenotype varies widely even in the (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between genotypes and the clinical disease phenotype.

Methods: One-hundred-and-sixteen homozygous patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for and . The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers.

Results: Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this variant (rs41266431), homozygous G variant carriers ( = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, < 0.040) and survival to end-stage lung disease was lower ( < 0.029). The frequency of colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, < 0.052) and sputum leukocytes (2305/437.5 pg/ml, < 0.025) were higher for the G/G genotype.

Conclusions: In carriers of the A allele (27.6%) the variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the genotype.

Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.
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http://dx.doi.org/10.3389/fgene.2020.570403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655539PMC
October 2020

Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study.

Int J Epidemiol 2021 05;50(2):475-484

Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design.

Methods: We conducted a cohort study in twins (7-12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden.

Results: Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively).

Conclusions: Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.
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http://dx.doi.org/10.1093/ije/dyaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248483PMC
May 2021

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition.

Int J Mol Sci 2020 Sep 10;21(18). Epub 2020 Sep 10.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.

A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (, and ), which can influence the proteins' structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.
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http://dx.doi.org/10.3390/ijms21186627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554776PMC
September 2020

International severe asthma registry (ISAR): protocol for a global registry.

BMC Med Res Methodol 2020 08 14;20(1):212. Epub 2020 Aug 14.

Allergy Centre, Tampere University Hospital and Tampere University, Tampere, Finland.

Background: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour.

Methods: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders.

Conclusions: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medicine, with the overarching aim of improving primary and secondary care of adults with severe asthma globally.
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http://dx.doi.org/10.1186/s12874-020-01065-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439682PMC
August 2020

Association between C reactive protein and microvascular and macrovascular dysfunction in sub-Saharan Africans with and without diabetes: the RODAM study.

BMJ Open Diabetes Res Care 2020 07;8(1)

Public Health, Amsterdam University Medical Centres, Amsterdam, The Netherlands.

Introduction: Although inflammation assessed by elevated C reactive protein (CRP) concentration is known to be associated with risk of cardiovascular disease, its association with microvascular and macrovascular dysfunction in diabetes and non-diabetes remains unclear. We examined the association between CRP and diabetes and associated microvascular and macrovascular dysfunction in sub-Saharan Africans with and without diabetes.

Research Design And Methods: Cross-sectional analyses of baseline data from the multicenter RODAM study (Research on Obesity and Diabetes among African Migrants) including 5248 Ghanaians (583 with diabetes, 4665 without diabetes) aged 25-70 years were done. Logistic regression analyses were used to examine the associations between CRP Z-scores and diabetes and microvascular (nephropathy) and macrovascular (peripheral artery disease (PAD)) dysfunction, with adjustments for age, sex, site of residence, smoking, body mass index, systolic blood pressure, and low-density lipoprotein cholesterol.

Results: In the fully adjusted models, higher CRP concentration was significantly associated with diabetes (adjusted OR 1.13; 95% CI 1.05 to 1.21, p=0.002). In participants with diabetes, higher CRP concentration was associated with PAD (1.19; 1.03 to 1.41, p=0.046) but not nephropathy (1.13; 0.97 to 1.31, p=0.120). Among participants without diabetes, higher CRP concentration was associated with higher odds of PAD (1.10; 1.01 to 1.21, p=0.029) and nephropathy (1.12; 1.04 to 1.22, p=0.004).

Conclusions: In this study, higher CRP concentration was associated with higher odds of diabetes in sub-Saharan Africans. Also, higher CRP concentration was associated with higher odds of nephropathy and PAD in non-diabetes and higher odds of PAD in diabetes. CRP may be an important marker for assessment of risk of diabetes and risk for PAD and nephropathy in sub-Saharan Africans with and without diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2020-001235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365428PMC
July 2020

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Circulation 2020 Aug 13;142(6):546-555. Epub 2020 Jul 13.

Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493828PMC
August 2020
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