Publications by authors named "Judith M Vonk"

202 Publications

A Mendelian randomization cytokine screen reveals IL-13 as causal factor in risk of severe COVID-19.

J Infect 2022 May 23. Epub 2022 May 23.

Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1016/j.jinf.2022.05.024DOI Listing
May 2022

High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.

J Heart Lung Transplant 2022 06 16;41(6):765-772. Epub 2022 Mar 16.

Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address:

Background: Serological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression.

Methods: The humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson's correlation coefficient was calculated to correlate serological responses to TTV load.

Results: Humoral responses to COVID-19 vaccination were observed in 41 of 103 (40%) LTR at 28 days after the second vaccination. Sixty-two of 103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation.

Conclusions: This study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response.
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http://dx.doi.org/10.1016/j.healun.2022.03.006DOI Listing
June 2022

Increased genetic contribution to wellbeing during the COVID-19 pandemic.

PLoS Genet 2022 05 19;18(5):e1010135. Epub 2022 May 19.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Physical and mental health are determined by an interplay between nature, for example genetics, and nurture, which encompasses experiences and exposures that can be short or long-lasting. The COVID-19 pandemic represents a unique situation in which whole communities were suddenly and simultaneously exposed to both the virus and the societal changes required to combat the virus. We studied 27,537 population-based biobank participants for whom we have genetic data and extensive longitudinal data collected via 19 questionnaires over 10 months, starting in March 2020. This allowed us to explore the interaction between genetics and the impact of the COVID-19 pandemic on individuals' wellbeing over time. We observe that genetics affected many aspects of wellbeing, but also that its impact on several phenotypes changed over time. Over the course of the pandemic, we observed that the genetic predisposition to life satisfaction had an increasing influence on perceived quality of life. We also estimated heritability and the proportion of variance explained by shared environment using variance components methods based on pedigree information and household composition. The results suggest that people's genetic constitution manifested more prominently over time, potentially due to social isolation driven by strict COVID-19 containment measures. Overall, our findings demonstrate that the relative contribution of genetic variation to complex phenotypes is dynamic rather than static.
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http://dx.doi.org/10.1371/journal.pgen.1010135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9119461PMC
May 2022

Quantile regression to examine the association of air pollution with subclinical atherosclerosis in an adolescent population.

Environ Int 2022 Jun 10;164:107285. Epub 2022 May 10.

Institute for Risk Assessment Sciences, Utrecht University, The Netherlands. Electronic address:

Background: Air pollution has been associated with carotid intima-media thickness test (CIMT), a marker of subclinical atherosclerosis. To our knowledge, this is the first study to report an association between ambient air pollution and CIMT in a younger adolescent population.

Objective: To investigate the associations beyond standard mean regression by using quantile regression to explore if associations occur at different percentiles of the CIMT distribution.

Methods: We measured CIMT cross-sectionally at the age of 16 years in 363 adolescents participating in the Dutch PIAMA birth cohort. We fit separate quantile regressions to examine whether the associations of annual averages of nitrogen dioxide (NO), fine particulate matter (PM), PM absorbance (a marker for black carbon), PM and ultrafine particles up to age 14 assigned at residential addresses with CIMT varied across deciles of CIMT. False discovery rate corrections (FDR, p < 0.05 for statistical significance) were applied for multiple comparisons. We report quantile regression coefficients that correspond to an average change in CIMT (µm) associated with an interquartile range increase in the exposure.

Results: PM absorbance exposure at birth was statistically significantly (FDR < 0.05) associated with a 6.23 µm (95% CI: 0.15, 12.3) higher CIMT per IQR increment in PM absorbance in the 10th quantile of CIMT but was not significantly related to other deciles within the CIMT distribution. For NO exposure we found similar effect sizes to PM absorbance, but with much wider confidence intervals. PM exposure was weakly positively associated with CIMT while PM and ultrafine did not display any consistent patterns.

Conclusions: Early childhood exposure to ambient air pollution was suggestively associated with the CIMT distribution during adolescence. Since CIMT increases with age, mitigation strategies to reduce traffic-related air pollution early in life could possibly delay atherosclerosis and subsequently CVD development later in life.
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http://dx.doi.org/10.1016/j.envint.2022.107285DOI Listing
June 2022

Pulmonary Function and Blood DNA Methylation: A Multi-Ancestry Epigenome-Wide Association Meta-Analysis.

Am J Respir Crit Care Med 2022 May 10. Epub 2022 May 10.

University of British Columbia, Department of Medicine, Division of Respiratory Medicine, Vancouver, British Columbia, Canada.

Rationale: Methylation integrates factors present at birth and modifiable across life that can influence pulmonary function. Studies are limited in scope and replication.

Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function.

Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multi-ancestry epigenome-wide meta-analyses (17,503 individuals: 14,761 European; 2,549 African; and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics.

Measurements And Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (FDR<0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to COPD (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that EWAS signals capture causal regulatory genomic loci.

Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies providing insights into lung pathogenesis. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202108-1907OCDOI Listing
May 2022

Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.

Environ Res 2022 Sep 30;212(Pt C):113360. Epub 2022 Apr 30.

Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences and Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO; NOx), ozone (O), and sulfur dioxide (SO) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (P > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.
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http://dx.doi.org/10.1016/j.envres.2022.113360DOI Listing
September 2022

Air pollution susceptibility in children with asthma and obesity: tidal volume as key player?

Eur Respir J 2022 03 3;59(3). Epub 2022 Mar 3.

Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1183/13993003.02505-2021DOI Listing
March 2022

Predicting the course of asthma from childhood until early adulthood.

Curr Opin Allergy Clin Immunol 2022 04;22(2):115-122

Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital.

Purpose Of Review: To communicate recent insights about the natural history of childhood asthma, with a focus on prediction of persistence and remission of childhood asthma, up to early adulthood.

Recent Findings: Lung function around the age of 8-9 years is the strongest predictor: obstructive lung function predicts asthma persistence up to early adulthood, whereas normal lung function predicts remission. The ability to predict asthma remission improves when lung function is combined with blood eosinophil levels and degree of bronchial hyperresponsiveness. Interventions, such as inhaled corticosteroids and immunotherapy do not appear to alter the course of asthma. Epigenetic studies have revealed potential novel biomarkers of asthma remission, such as micro-RNA patterns in blood. Specifically, lower serum levels of mi-R221-5p, which is associated with lower IL-6 release and eosinophilic inflammation, predict remission. Higher levels of blood DNA-methylation of a CpG site in Peroxisomal Biogenesis Factor 11 Beta were associated with asthma remission.

Summary: Lung function, allergic comorbidity and polysensitization in childhood predict the course of asthma. Recent epigenetic studies have provided a better understanding of underlying pathological processes in asthma remission, which may be used to improve prediction or develop novel treatments aimed at altering the course of asthma.
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http://dx.doi.org/10.1097/ACI.0000000000000810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915994PMC
April 2022

Spirometric phenotypes from early childhood to young adulthood: a Chronic Airway Disease Early Stratification study.

ERJ Open Res 2021 Oct 6;7(4). Epub 2021 Dec 6.

National Heart and Lung Institute, Imperial College London, London, UK.

Background: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts.

Methods: We studied 49 334 participants from 14 population-based cohorts in different age groups (≤10, >10-15, >15-20, >20-25 years, and overall, 5-25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV/FVC z-score ≥LLN, and FVC z-score
Results: The prevalence of obstructive and restrictive phenotypes varied from 3.2-10.9% and 1.8-7.7%, respectively, without clear age trends. A diagnosis of asthma (adjusted odds ratio (aOR=2.55, 95% CI 2.14-3.04), preterm birth (aOR=1.84, 1.27-2.66), maternal smoking during pregnancy (aOR=1.16, 95% CI 1.01-1.35) and family history of asthma (aOR=1.44, 95% CI 1.25-1.66) were associated with a higher prevalence of obstructive, but not restrictive, phenotype across ages (5-25 years). A higher current body mass index (BMI was more often observed in those with the obstructive phenotype but less in those with the restrictive phenotype (aOR=1.05, 95% CI 1.03-1.06 and aOR=0.81, 95% CI 0.78-0.85, per kg·m increase in BMI, respectively). Current smoking was associated with the obstructive phenotype in participants older than 10 years (aOR=1.24, 95% CI 1.05-1.46).

Conclusion: Obstructive and restrictive phenotypes were found to be relatively prevalent during childhood, which supports the early origins concept. Several well-known respiratory risk factors were associated with the obstructive phenotype, whereas only low BMI was associated with the restrictive phenotype, suggesting different underlying pathobiology of these two phenotypes.
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http://dx.doi.org/10.1183/23120541.00457-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646001PMC
October 2021

Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.

Nat Commun 2021 11 16;12(1):6618. Epub 2021 Nov 16.

Department of Twins Research and Genetic Epidemiology, King's College London, London, UK.

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
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http://dx.doi.org/10.1038/s41467-021-26783-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8595373PMC
November 2021

Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease: a cross-sectional analysis of ten population-based studies.

Lancet Respir Med 2022 01 4;10(1):83-94. Epub 2021 Oct 4.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; COPD Centre, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements.

Methods: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year.

Findings: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001).

Interpretation: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity.

Funding: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme.
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http://dx.doi.org/10.1016/S2213-2600(21)00313-1DOI Listing
January 2022

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 09 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612069PMC
September 2021

The dilemma of open or double-blind food challenges in diagnosing food allergy in children: Design of the ALDORADO trial.

Pediatr Allergy Immunol 2022 01 9;33(1):e13654. Epub 2021 Sep 9.

Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: It is of major importance to diagnose food allergy accurately. Current guidelines support the use of oral food challenges to do so. The double-blind placebo-controlled food challenge (DBPCFC) has been regarded as the 'gold standard' for decades. However, DBPCFCs are costly, and time- and resource-intensive procedures. Structural implementation of less demanding open food challenges will only find support if research demonstrates that their outcome is comparable to DBPCFC, yet this has been proven difficult to investigate.

Methods: We performed a literature review to investigate the diagnostic accuracy of oral food challenges and interviewed 19 parents of children with proven or suspected food allergy about the design of a trial to study this.

Results: An overview of the dilemma of diagnosing food allergy using oral food challenges, and the methodological issues and parents' opinions to study this. No comparative studies have been performed using the latest guidelines on oral food challenges.

Conclusions: There is an urgent need to investigate the diagnostic accuracy of different oral food challenge protocols. We present the rationale and design of the ALDORADO trial (ALlergy Diagnosed by Open oR DOuble-blind food challenge) that has been set up to investigate whether the outcome of the open food challenge is comparable to DBPCFC.
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http://dx.doi.org/10.1111/pai.13654DOI Listing
January 2022

Ultrafine particles, particle components and lung function at age 16 years: The PIAMA birth cohort study.

Environ Int 2021 12 10;157:106792. Epub 2021 Aug 10.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands. Electronic address:

Background: Particulate matter (PM) air pollution exposure has been linked to lung function in adolescents, but little is known about the relevance of specific PM components and ultrafine particles (UFP).

Objectives: To investigate the associations of long-term exposure to PM elemental composition and UFP with lung function at age 16 years.

Methods: For 706 participants of a prospective Dutch birth cohort, we assessed associations of forced expiratory volume in 1 s (FEV) and forced vital capacity (FVC) at age 16 with average exposure to eight elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc) in PM and PM, as well as UFP during the preceding years (age 13-16 years) estimated by land-use regression models. After assessing associations for each pollutant individually using linear regression models with adjustment for potential confounders, independence of associations with different pollutants was assessed in two-pollutant models with PM mass and NO, for which associations with lung function have been reported previously.

Results: We observed that for most PM elemental components higher exposure was associated with lower FEV, especially PM sulfur [e.g. adjusted difference -2.23% (95% confidence interval (CI) -3.70 to -0.74%) per interquartile range (IQR) increase in PM sulfur]. The association with PM sulfur remained after adjusting for PM mass. Negative associations of exposure to UFP with both FEV and FVC were observed [-1.06% (95% CI: -2.08 to -0.03%) and -0.65% (95% CI: -1.53 to 0.23%), respectively per IQR increase in UFP], but did not persist in two-pollutant models with NO or PM.

Conclusions: Long-term exposure to sulfur in PM may result in lower FEV at age 16. There is no evidence for an independent effect of UFP exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106792DOI Listing
December 2021

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility.

PLoS One 2021 11;16(8):e0255402. Epub 2021 Aug 11.

Helix OpCo LLC, San Mateo, California, United States of America.

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255402PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357137PMC
August 2021

The sputum transcriptome better predicts COPD exacerbations after the withdrawal of inhaled corticosteroids than sputum eosinophils.

ERJ Open Res 2021 Jul 5;7(3). Epub 2021 Jul 5.

Dept of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Introduction: Continuing inhaled corticosteroid (ICS) use does not benefit all patients with COPD, yet it is difficult to determine which patients may safely sustain ICS withdrawal. Although eosinophil levels can facilitate this decision, better biomarkers could improve personalised treatment decisions.

Methods: We performed transcriptional profiling of sputum to explore the molecular biology and compared the predictive value of an unbiased gene signature sputum eosinophils for exacerbations after ICS withdrawal in COPD patients. RNA-sequencing data of induced sputum samples from 43 COPD patients were associated with the time to exacerbation after ICS withdrawal. Expression profiles of differentially expressed genes were summarised to create gene signatures. In addition, we built a Bayesian network model to determine coregulatory networks related to the onset of COPD exacerbations after ICS withdrawal.

Results: In multivariate analyses, we identified a gene signature (, , , , , ) associated with the time to first exacerbation after ICS withdrawal. The addition of this gene signature to a multiple Cox regression model explained more variance of time to exacerbations compared to a model using sputum eosinophils. The gene signature correlated with sputum eosinophil as well as macrophage cell counts. The Bayesian network model identified three coregulatory gene networks as well as sex to be related to an early late/nonexacerbation phenotype.

Conclusion: We identified a sputum gene expression signature that exhibited a higher predictive value for predicting COPD exacerbations after ICS withdrawal than sputum eosinophilia. Future studies should investigate the utility of this signature, which might enhance personalised ICS treatment in COPD patients.
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http://dx.doi.org/10.1183/23120541.00097-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255541PMC
July 2021

Psychosocial work factors and blood pressure among 63 800 employees from The Netherlands in the Lifelines Cohort Study.

J Epidemiol Community Health 2022 01 2;76(1):60-66. Epub 2021 Jul 2.

Department of Health Sciences, Community and Occupational Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Objectives: Previous studies on the association between psychosocial work factors and blood pressure mainly focused on specific occupations or populations and had limited sample sizes. We, therefore, investigated the associations between psychosocial work factors and blood pressure in a large general working population in the Netherlands.

Methods: We included 63 800 employees from the Netherlands, aged 18-65 years, with blood pressure measurements and a reliable job code at baseline. Psychosocial work factors (job strain, effort-reward imbalance (ERI) and emotional demands) in the current job were estimated with three recently developed psychosocial job exposure matrices. To examine the associations, regression analyses adjusted for covariates (age, sex, body mass index, education, monthly income, pack-years, smoking, alcohol consumption and antihypertensive medication (not included for hypertension)) were performed.

Results: Higher job strain was associated with higher systolic blood pressure (SBP) (B (regression coefficients) (95% CI) 2.14 (1.23 to 3.06)) and diastolic blood pressure (DBP) (B (95% CI) 1.26 (0.65 to 1.86)) and with higher odds of hypertension (OR (95% CI) 1.43 (1.17 to 1.74)). Higher ERI was associated with higher DBP (B (95% CI) 4.37 (3.05 to 5.68)), but not with SBP or hypertension. Higher emotional demands were associated with lower SBP (B (95% CI) -0.90 (-1.14 to -0.66)) and lower odds of hypertension ((OR) (95% CI) 0.91 (0.87 to 0.96)).

Conclusions: In the general working population, employees in jobs with high job strain and ERI have higher blood pressure compared with employees with low job strain and ERI. Emotional demands at work are inversely associated with blood pressure.
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http://dx.doi.org/10.1136/jech-2021-216678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666827PMC
January 2022

Long-term exposure to fine particulate matter, lung function and cognitive performance: A prospective Dutch cohort study on the underlying routes.

Environ Res 2021 10 18;201:111533. Epub 2021 Jun 18.

Institute of Sociology and Demography, University of Rostock, Rostock, Germany; German Center for Neurodegenerative Diseases, Bonn, Germany.

Background: Exposure to fine particulate matter and black carbon is related to cognitive impairment and poor lung function, but less is known about the routes taken by different types of air pollutants to affect cognition.

Objectives: We tested two possible routes of fine particulate matter (PM) and black carbon (BC) in impairing cognition, and evaluated their importance: a direct route over the olfactory nerve or the blood stream, and an indirect route over the lung.

Methods: We used longitudinal observational data for 49,705 people aged 18+ from 2006 to 2015 from the Dutch Lifelines cohort study. By linking current home addresses to air pollution exposure data from ELAPSE in 2010, long-term average exposure to PM and BC was assessed. Lung function was measured by spirometry and Global Initiative (GLI) z-scores of forced expiratory volume in 1s (FEV) and forced vital capacity (FVC) were calculated. Cognitive performance was measured by cognitive processing time (CPT) assessed by the Cogstate Brief Battery. Linear structural equation modeling was performed to test direct/indirect associations.

Results: Higher exposure to PM but not BC was related to higher CPT and slower cognitive processing speed [Total Effect PM: FEV model = 8.31 × 10 (95% CI: 5.71 × 10, 10.91 × 10), FVC model = 8.30 × 10 (95% CI: 5.69 × 10, 10.90 × 10)]. The direct association of PM constituted more than 97% of the total effect. Mediation by lung function was low for PM with a mediated proportion of 1.32% (FEV) and 2.05% (FVC), but higher for BC (7.01% and 13.82% respectively).

Discussion: Our results emphasise the importance of the lung acting as a mediator in the relationship between both exposure to PM and BC, and cognitive performance. However, higher exposure to PM was mainly directly associated with worse cognitive performance, which emphasises the health-relevance of fine particles due to their ability to reach vital organs directly.
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http://dx.doi.org/10.1016/j.envres.2021.111533DOI Listing
October 2021

Long-term outcomes of atrioventricular septal defect and single ventricle: A multicenter study.

J Thorac Cardiovasc Surg 2022 Mar 18;163(3):1166-1175. Epub 2021 May 18.

Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objective: The study objective was to analyze survival and incidence of Fontan completion of patients with single-ventricle and concomitant unbalanced atrioventricular septal defect.

Methods: Data from 4 Dutch and 3 Belgian institutional databases were retrospectively collected. A total of 151 patients with single-ventricle atrioventricular septal defect were selected; 36 patients underwent an atrioventricular valve procedure (valve surgery group). End points were survival, incidence of Fontan completion, and freedom from atrioventricular valve reoperation.

Results: Median follow-up was 13.4 years. Cumulative survival was 71.2%, 70%, and 68.5% at 10, 15, and 20 years, respectively. An atrioventricular valve procedure was not a risk factor for mortality. Patients with moderate-severe or severe atrioventricular valve regurgitation at echocardiographic follow-up had a significantly worse 15-year survival (58.3%) compared with patients with no or mild regurgitation (89.2%) and patients with moderate regurgitation (88.6%) (P = .033). Cumulative incidence of Fontan completion was 56.5%, 71%, and 77.6% at 5, 10, and 15 years, respectively. An atrioventricular valve procedure was not associated with the incidence of Fontan completion. In the valve surgery group, freedom from atrioventricular valve reoperation was 85.7% at 1 year and 52.6% at 5 years.

Conclusions: The long-term survival and incidence of Fontan completion in our study were better than previously described for patients with single-ventricle atrioventricular septal defect. A concomitant atrioventricular valve procedure did not increase the mortality rate or decrease the incidence of Fontan completion, whereas patients with moderate-severe or severe valve regurgitation at follow-up had a worse survival. Therefore, in patients with single-ventricle atrioventricular septal defect when atrioventricular valve regurgitation exceeds a moderate degree, the atrioventricular valve should be repaired.
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http://dx.doi.org/10.1016/j.jtcvs.2021.05.015DOI Listing
March 2022

Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years.

Blood Adv 2021 04;5(8):2115-2122

Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Clonal hematopoiesis (CH), characterized by a fraction of peripheral blood cells carrying an acquired genetic variant, emerges with age. Although in general CH is associated with increased mortality and morbidity, no higher risk of death was observed for individuals ≥80 years. Here, we investigated CH in 621 individuals aged ≥80 years from the population-based LifeLines cohort. Sensitive error-corrected sequencing of 27 driver genes at a variant allele frequency ≥1% revealed CH in the majority (62%) of individuals, independent of gender. The observed mutational spectrum was dominated by DNMT3A and TET2 variants, which frequently (29%) displayed multiple mutations per gene. In line with previous results in individuals ≥80 years, the overall presence of CH did not associate with a higher risk of death (hazard ratio, 0.91; 95% confidence interval, 0.70-1.18; P = .48). Being able to assess the causes of death, we observed no difference between individuals with or without CH, except for deaths related to hematological malignancies. Interestingly, comparison of mutational spectra confined to DNMT3A and TET2 vs spectra containing other mutated genes, showed a higher risk of death when mutations other than DNMT3A or TET2 were present (hazard ratio, 1.48; 95% confidence interval, 1.06-2.08; P = .025). Surprisingly, no association of CH with cardiovascular morbidity was found, irrespective of clone size. Further, CH associated with chronic obstructive pulmonary disease. Data on estimated exposure to DNA damaging toxicities (ie, smoking, a history of cancer [as a proxy for previous genotoxic therapy], and job-related pesticide exposure) showed an association with spliceosome and ASXL1 variants, but not with DNMT3A and TET2 variants.
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http://dx.doi.org/10.1182/bloodadvances.2020004062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095141PMC
April 2021

Residential PM exposure and the nasal methylome in children.

Environ Int 2021 08 16;153:106505. Epub 2021 Apr 16.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Rationale: PMinduced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known.

Objectives: We aimed to study associations of fine particulate matter PM exposure with DNA methylation in nasal cells.

Methods: We conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina MethylationEPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA).

Results: In adjusted analyses, we found 362 CpGs associated with 1-year PM (FDR < 0.05), 20 CpGs passing Bonferroni correction (P < 7.0x10) and 10 Differentially Methylated Regions (DMRs). In 445 PIAMA participants (mean age 16.3 years) 11 of 203 available CpGs replicated at P < 0.05. We observed differential DNAm at/near genes implicated in cell cycle, immune and inflammatory responses. There were no CpGs or regions associated with PM levels at 1-day, 1-week, or 1-month prior to sample collection, although 2 CpGs were associated with past 3-month PM.

Conclusion: We observed wide-spread DNAm variability associated with average past year PM exposure but we did not detect associations with shorter-term exposure. Our results suggest that nasal DNAm marks reflect chronic air pollution exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8823376PMC
August 2021

Asthma, bronchial hyperresponsiveness, allergy and lung function development until early adulthood: A systematic literature review.

Pediatr Allergy Immunol 2021 08 13;32(6):1238-1254. Epub 2021 May 13.

Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: It is unclear in which periods of life lung function deficits develop, and whether these are affected by risk factors such as asthma, bronchial hyper-responsiveness (BHR) and allergic comorbidity. The goal of this systematic review was to identify temporal associations of asthma, BHR and allergic comorbidity with large and small lung function development from birth until peak function in early adulthood.

Methods: We searched MEDLINE, EMBASE, Web of Science and CINAHL for papers published before 01.01.2020 on risk factors and lung function measurements of large and small airways. Studies were required to report lung function at any time point or interval from birth until peak lung function (age 21-26) and include at least one candidate risk factor.

Results: Of the 45 papers identified, 44 investigated cohorts and one was a clinical trial with follow-up. Asthma, wheezing, BHR and allergic sensitization early in life and to multiple allergens were associated with a lower lung function growth of large and small airways during early childhood compared with the control populations. Lung function development after childhood in subjects with asthma or persistent wheeze, although continuing to grow at a lower level, largely tracked parallel to non-affected individuals until peak function was attained.

Clinical Implications And Future Research: Deficits in lung function growth develop in early childhood, and children with asthma, BHR and early-life IgE (poly)sensitization are at risk. This period is possibly a critical window of opportunity to identify at-risk subjects and provide treatment aimed at preventing long-term sequelae of lung function.
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http://dx.doi.org/10.1111/pai.13516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453965PMC
August 2021

Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.

Pediatr Pulmonol 2021 07 22;56(7):1896-1905. Epub 2021 Mar 22.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Exposure to violence (ETV) or chronic stress may influence asthma through unclear mechanisms.

Methods: Epigenome-wide association study (EWAS) of ETV or chronic stress measures and DNA methylation in nasal epithelium from 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed four measures of ETV and chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by p value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).

Results: Three CpGs (in SNN, PTPRN2, and LINC01164) were associated with maternal perceived stress or gun violence (p = 1.28-3.36 × 10 ), but not with atopic asthma, in EVA-PR. In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence measures in EVA-PR, 12 CpGs (in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4, and ANAPC13) were associated with atopic asthma at FDR-p < .05.

Conclusions: Pending confirmation in longitudinal studies, our findings suggest that nasal epithelial methylation markers associated with measures of ETV and chronic stress may be linked to atopic asthma in children and adolescents.
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http://dx.doi.org/10.1002/ppul.25372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217314PMC
July 2021

Lifelines COVID-19 cohort: investigating COVID-19 infection and its health and societal impacts in a Dutch population-based cohort.

BMJ Open 2021 03 17;11(3):e044474. Epub 2021 Mar 17.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Purpose: The Lifelines COVID-19 cohort was set up to assess the psychological and societal impacts of the COVID-19 pandemic and investigate potential risk factors for COVID-19 within the Lifelines prospective population cohort.

Participants: Participants were recruited from the 140 000 eligible participants of Lifelines and the Lifelines NEXT birth cohort, who are all residents of the three northern provinces of the Netherlands. Participants filled out detailed questionnaires about their physical and mental health and experiences on a weekly basis starting in late March 2020, and the cohort consists of everyone who filled in at least one questionnaire in the first 8 weeks of the project. FINDINGS TO DATE: >71 000 unique participants responded to the questionnaires at least once during the first 8 weeks, with >22 000 participants responding to seven questionnaires. Compiled questionnaire results are continuously updated and shared with the public through the Corona Barometer website. Early results included a clear signal that younger people living alone were experiencing greater levels of loneliness due to lockdown, and subsequent results showed the easing of anxiety as lockdown was eased in June 2020.

Future Plans: Questionnaires were sent on a (bi)weekly basis starting in March 2020 and on a monthly basis starting July 2020, with plans for new questionnaire rounds to continue through 2020 and early 2021. Questionnaire frequency can be increased again for subsequent waves of infections. Cohort data will be used to address how the COVID-19 pandemic developed in the northern provinces of the Netherlands, which environmental and genetic risk factors predict disease susceptibility and severity and the psychological and societal impacts of the crisis. Cohort data are linked to the extensive health, lifestyle and sociodemographic data held for these participants by Lifelines, a 30-year project that started in 2006, and to data about participants held in national databases.
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http://dx.doi.org/10.1136/bmjopen-2020-044474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977080PMC
March 2021

Airborne occupational exposures and the risk of developing respiratory symptoms and airway obstruction in the Lifelines Cohort Study.

Thorax 2021 Mar 2. Epub 2021 Mar 2.

University Medical Center Groningen, Department of Epidemiology, University of Groningen, Groningen, Netherlands.

Objectives: To date, only a few studies have investigated the associations between occupational exposures and respiratory outcomes longitudinally in the general population. We investigated the associations between occupational exposures and the development of respiratory symptoms and airway obstruction in the Lifelines Cohort Study.

Methods: We included 35 739 occupationally active subjects with data on chronic cough, chronic phlegm, chronic bronchitis or airway obstruction at baseline and approximately 4.5 years follow-up. Exposures to biological dust, mineral dust, gases/fumes, pesticides, solvents and metals in the current job at baseline were estimated with the ALOHA+job-exposure matrix (JEM). Airway obstruction was defined as FEV/FVC below the lower limit of normal. Logistic regression analysis adjusted for baseline covariates was used to investigate the associations.

Results: At follow-up, 1888 (6.0%), 1495 (4.7%), 710 (2.5%) and 508 (4.5%) subjects had developed chronic cough, chronic phlegm, chronic bronchitis and airway obstruction, respectively. High exposure to biological dust was associated with a higher odds to develop chronic cough and chronic bronchitis. High exposure to pesticides was associated with a higher odds for the development of all respiratory symptoms and airway obstruction. In the multiple exposures analyses, only the association between pesticides exposure and respiratory symptoms remained.

Conclusions: Subjects exposed to high pesticides had a higher odds to develop respiratory symptoms on average 4.5 years later. Control measures should be taken to reduce pesticides exposure among the working population to prevent respiratory symptoms and airway obstruction.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311115PMC
March 2021

Mental Well-being and General Health in Adolescents with Asthma: The Prevention and Incidence of Asthma and Mite Allergy Birth Cohort Study.

J Pediatr 2021 06 4;233:198-205.e2. Epub 2021 Feb 4.

Center for Prevention and Health Services Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

Objectives: To assess whether adolescents with asthma experience a lower mental well-being and lower general health than their peers without asthma.

Study Design: Data from the Prevention and Incidence of Asthma and Mite Allergy study were used. At the ages of 11, 14, 17, and 20 years, 2651, 2522, 2094, and 2206 participants, respectively, completed questionnaires. Their parents completed questionnaires at the ages of 11 (n = 2660), 14 (n = 2338), and 17 years (n = 1872). Asthma was defined according to the Mechanisms of the Development of Allergy criteria. Mental well-being was measured using the Mental Health Index-5 and was reported by the adolescents. General health, measured on a 4-point Likert scale, was reported by the adolescents and their parents. We estimated associations of asthma with mental well-being and perceived general health using generalized estimating equations.

Results: At ages 11, 14, 17, and 20 years, 6.7%, 6.9%, 5.0%, and 6.6%, respectively, of the adolescents had asthma. Adolescents with asthma did not score differently on the Mental Health Index than their peers without asthma. Adolescents with asthma were less likely to experience good or excellent health than their peers without asthma (aOR, 0.37; 95% CI, 0.26-0.51 for intermittent asthma and 0.33; 95% CI, 0.25-0.41 for persistent asthma). These results remain similar across the different ages.

Conclusions: The mental well-being of adolescents with asthma is similar to that of their peers without asthma, although adolescents with asthma are less likely to perceive a good or excellent general health.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.074DOI Listing
June 2021

Grandmaternal smoking, asthma and lung function in the offspring: the Lifelines cohort study.

Thorax 2021 05 4;76(5):441-447. Epub 2021 Feb 4.

Department of Epidemiology, GRIAC Research Institute, University Medical Center Groningen, Groningen, The Netherlands

Background/objective: Limited research exists regarding the association between grandmaternal smoking during pregnancy and the risk for asthma and altered lung function in grandchildren. This study aimed to investigate this association in a three-generation design.

Methods: 37 291 participants (25 747 adults and 11 544 children) were included from the Lifelines study, a prospective longitudinal three generation cohort study in The Netherlands. Spirometry was available in 69.5% and 61.1% of the included adults and children. Logistic and linear regression were used to analyse the association between grandmaternal smoking during pregnancy and (1) asthma, (2) early childhood asthma (ie, onset before 6 years) and (3) lung function level. Maternal and paternal grandmaternal smoking were studied separately and the analyses were stratified by adult/child and by gender. The analyses were adjusted for gender, current smoking, birth variables and socioeconomic status.

Results: In the adult population, maternal grandmaternal smoking during pregnancy was associated with a higher risk for asthma (OR (95% CI): 1.38 (1.06 to 1.79)), early childhood asthma (1.49 (95% CI 1.06 to 2.11)) and a lower FEV1/FVC% predicted (B (95% CI): -1.04 (-1.91 to -0.16) in men. These findings were not observed in a separate analysis of children that participated in this study. There was also no significant association between paternal grandmaternal smoking and asthma/lung function.

Conclusion: Maternal grandmaternal smoking during pregnancy is associated with higher asthma risk and lower lung function in male grandchildren and a reverse effect in male grandchildren of subsequent generations. Our study highlights the deep-rooted effects of tobacco smoking across generations.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070652PMC
May 2021

Blood eosinophils associate with reduced lung function growth in adolescent asthmatics.

Clin Exp Allergy 2021 04 16;51(4):556-563. Epub 2021 Jan 16.

Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen, Groningen, The Netherlands.

Background And Objective: Some children with asthma have low lung growth, putting them at increased risk for COPD later in life. However, it is currently not clear who will experience this adverse growth pattern. We therefore investigated the predictive role of blood eosinophils as a type 2 inflammation marker in lung growth, focusing on the presence and severity of asthma.

Methods: We investigated blood eosinophils and lung function growth (percentage of predicted values) using linear mixed models in children and adolescents from two longitudinal cohorts. One cohort was hospital-based and consisted of asthmatic children at their first outpatient clinic visit after referral by the general practitioner (n = 133, mean age 9.8), while the second was a general population-based birth cohort (PIAMA, asthma n = 52 and non-asthma n = 433, mean age 8.1). The hospital-based cohort had not been treated with inhaled corticosteroids (ICS) before referral.

Results: Subjects in the hospital-based asthma cohort had more severe asthma compared with the asthmatic subjects in the population-based cohort, defined by lower lung function levels and a higher prevalence of bronchial hyper-responsiveness. In the asthma cohort, higher blood eosinophil numbers were associated with less growth in FEV (estimated change in lung function per 1 unit increase in ln blood eosinophils (B): -0.66%/year (95% confidence interval (CI): -1.11 to -0.20, p < .01)) and FVC (B: -0.40%/year (95% CI: -0.75 to -0.05), p = .025)) during follow-up in adolescence (min 7, max 17 years). These associations were not observed in the general population-based birth cohort, regardless of asthma status during follow-up (age 8-16).

Conclusions And Clinical Relevance: Blood eosinophil counts in children with asthma not treated with ICS at referral were predictive of lower growth in FEV and FVC during follow-up in adolescence. Our findings indicate that this association is dependent on the degree of asthma severity. Future studies should address whether anti-eosinophilic treatments preserve lung function growth in children with asthma.
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http://dx.doi.org/10.1111/cea.13818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048657PMC
April 2021

Predicted values for the forced expiratory flow adjusted for forced vital capacity, a descriptive study.

ERJ Open Res 2020 Oct 14;6(4). Epub 2020 Dec 14.

University of Groningen, University Medical Centre Groningen, Dept of Pulmonary Diseases Groningen, The Netherlands.

Background: The forced expiratory flows (FEFs) towards the end of the expiration may be more sensitive in detecting peripheral airways obstruction compared to the forced expiratory volume in 1 s and forced vital capacity (FVC). However, they are highly variable. A partial solution is to adjust the FEFs for FVC (FEF/FVC). Here we provide reference equations for these adjusted FEFs at 25%, 50%, 75% and 25-75% of FVC, which are currently lacking.

Methods: We included pulmonary healthy, never-smoker adults; 14 472 subjects from Lifelines, a biobank for health research, and 338 subjects from the department's control cohorts (NORM and Fiddle). Reference equations were obtained by linear regression on 80% of the Lifelines dataset and validated on the remaining data. The best model was defined as the one with the highest adjusted R-value. The difference in variability between adjusted and unadjusted FEFs was evaluated using the coefficient of variation.

Results: For all adjusted FEFs, the best model contained age, height and weight. The adjustment improved the coefficient of variation of the FEF from 39% to 36% and from 43% to 40%, respectively, in males and females. The highest percentage of explained variance by the reference equation was obtained for FEF/FVC, 32%-38% for males, and 41%-46% for females, depending on the validation set.

Conclusion: We developed reference equations for FVC-adjusted FEF values. We demonstrated minimally yet significantly improved variability. Future studies in obstructive airway diseases should demonstrate whether it is worthwhile to use these (predicted) adjusted FEF values.
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http://dx.doi.org/10.1183/23120541.00426-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737427PMC
October 2020
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