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

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.

Risk of neuropsychiatric adverse events associated with varenicline treatment for smoking cessation among Dutch population: A sequence symmetry analysis.

PURPOSE: Varenicline is an effective treatment for smoking cessation. While clinical trials did not confirm a causal role, case reports suggested a possible link of varenicline with neuropsychiatric adverse drug events (NPAEs). This study aims to investigate the risk of NPAEs associated with varenicline initiation among the general population in a real-world setting. METHODS: We conducted a sequence symmetry analysis (SSA) based on the University of Groningen IADB.nl prescription database. We selected incident users of both varenicline and marker drugs for NPAEs, including depression, anxiety and sleep disorder within different time-intervals. Adjusted sequence ratios (aSR) were calculated for each time-interval. RESULTS: Within 365-days' time-interval 1066 patients were incident users of both varenicline and NPAE marker drugs. In total, 505 patients were prescribed varenicline before NPAE marker drugs and 561 vice versa (crude sequence ratio [cSR] 0.90, 95% CI: 0.80-1.02). After adjustments for trends in prescriptions, overall a null association was found (aSR 1.00, 95% CI: 0.89-1.13). Regarding specific NPAEs, no increased risks were found for depression nor anxiety within any time-interval. A small transient increased risk was found for sleep disorders, particularly in earlier time-intervals 3 and 6 months (aSRs 1.52, 95% CI: 1.10-2.11 and 1.45, 95% CI: 1.15-1.83, respectively). Subgroup and sensitivity analyses showed similar findings. CONCLUSIONS: Varenicline initiation was unlikely to be associated with an increased risk of taking anti-depressants nor anti-anxiety drugs. Yet a small, but statistically significant, transient association with drugs for sleep disorders was noticed, possibly associated with withdrawal symptoms caused by smoking cessation.

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

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 (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) 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 (PCochran's Q > 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 NO2 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.

Regional variation in lifestyle patterns and BMI in young children: the GECKO Drenthe cohort.

BACKGROUND: A better understanding of lifestyle behaviours of children < 7 years and the relation with childhood overweight is needed. The aim of our prospective study was to examine how lifestyle patterns in young children are associated with the development of childhood overweight. As ecological models suggest focusing on not only the child as an individual, but also their environment, we also considered the role of socio-economic status (SES) and spatial clustering of lifestyle and body mass index (BMI). METHODS: In 1792 children (aged 3-6 years) participating in the GECKO Drenthe cohort, diet, screen time, outdoor play and sleep were assessed by questionnaires and moderate-to-vigorous physical activity and sedentary time by accelerometry (Actigraph GT3X). At 10-11 years, height and weight were measured to calculate age- and sex-specific standardized BMI z-scores (zBMI). Lifestyle patterns were identified using principal component analysis. To assess spatial clustering for the lifestyle patterns and zBMI, we calculated the Global Moran's I statistic. Linear- and logistic regression models, taking into account SES, were performed to examine the association between the lifestyle patterns and the development of overweight. For the spatial analyses, we added spatial terms for the determinants, the outcome, and the error term. RESULTS: Three lifestyle patterns were identified: (1) 'high activity', (2) 'low screen time, high sleep and healthy diet', and (3) 'high outdoor play'. No associations were observed between the 'high activity' or 'high outdoor play' patterns at young age with the development of childhood overweight (all p > 0.05). In contrast, children who adhered to the 'low screen time, high sleep and healthy diet' pattern had lower odds to become overweight and a lower zBMI at 10-11 years (odds ratio [95% CI] = 0.766 [0.65; 0.90]). These findings remained similar after taking SES into account. Regarding the spatial analyses, we found spatial clustering of zBMI, but no spatial clustering of the lifestyle patterns. CONCLUSIONS: Low screen time, high sleep duration and a healthy diet cluster into a pattern that seems favourable in the prevention of childhood overweight, independent of individual SES. The spatial analyses suggest that there are likely other neighbourhood factors that contribute to the spatial clustering of childhood overweight.

Real-World Effects of Antibiotic Treatment on Acute COPD Exacerbations in Outpatients: A Cohort Study under the PharmLines Initiative.

BACKGROUND: Although antibiotic treatment is recommended for acute exacerbations of chronic obstructive pulmonary disease (AECOPD), its value in real-world settings is still controversial. OBJECTIVES: This study aimed to evaluate the short- and long-term effects of antibiotic treatment on AECOPD outpatients. METHODS: A cohort study was conducted under the PharmLines Initiative. We included participants with a first recorded diagnosis of COPD who received systemic glucocorticoid treatment for an AECOPD episode. The exposed and reference groups were defined based on any antibiotic prescription during the AECOPD treatment. The short-term outcome was AECOPD treatment failure within 14-30 days after the index date. The long-term outcome was time to the next exacerbation. Adjustment for confounding was made using propensity scores. RESULTS: Of the 1,105 AECOPD patients, antibiotics were prescribed to 518 patients (46.9%) while 587 patients (53.1%) received no antibiotics. The overall antibiotic use was associated with a relative risk reduction of AECOPD treatment failure by 37% compared with the reference group (adjusted odds ratio [aOR] 0.63 [95% CI: 0.40-0.99]). Protective effects were similar for doxycycline, macrolides, and co-amoxiclav, although only the effect of doxycycline was statistically significant (aOR 0.53 [95% CI: 0.28-0.99]). No protective effect was seen for amoxicillin (aOR 1.49 [95% CI: 0.78-2.84]). The risk of and time to the next exacerbation was similar for both groups. CONCLUSION: Overall, antibiotic treatment, notably with doxycycline, supplementing systemic glucocorticoids reduces short-term AECOPD treatment failure in real-world outpatient settings. No long-term beneficial effects of antibiotic treatment on AECOPD were found for the prevention of subsequent exacerbations.

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression.

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

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

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 FEV1/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.

Airborne occupational exposures and inflammatory biomarkers in the Lifelines cohort study.

INTRODUCTION: Inflammatory biomarkers are associated with negative health outcomes. In this study, we investigated the associations between airborne occupational exposures and levels and changes in inflammatory biomarkers. METHODS: We included 79 604 adults at baseline from the Lifelines cohort of which 48 403 (60.8%) subjects were followed for a median of 4.5 years. Airborne occupational exposures at the current or last-held job at baseline were estimated with the occupational asthma-specific job-exposure matrix. Both in cross-sectional and longitudinal analyses, we used linear regression models (adjusted for age, sex, education, monthly income, body mass index, smoking, pack-years, asthma and anti-inflammatory medication) to investigate the associations between airborne occupational exposures (allergens, reactive chemicals, pesticides and micro-organisms) and inflammatory biomarkers (C reactive protein (CRP), eosinophils and neutrophils). RESULTS: In the cross-sectional analyses, exposure to allergens, reactive chemicals and micro-organisms was associated with a lower (Log) CRP level (B(95% CI)=-0.05 (-0.08 to -0.02),-0.05(-0.08 to -0.02) and -0.09(-0.16 to -0.02), respectively). Likewise, exposure to allergens, reactive chemicals, pesticides and micro-organisms was associated with a lower (log) neutrophils count (-0.01 (-0.02 to -0.01), -0.01 (-0.02 to -0.01),-0.02 (-0.04 to -0.01) and -0.02(-0.03 to -0.01), respectively). No association between airborne occupational exposures and eosinophils count was found. In the longitudinal analyses, no association between airborne occupational exposures and changes in inflammatory biomarkers was found. CONCLUSIONS: At baseline, airborne occupational exposures are inversely associated with inflammation; no effect of occupational exposures on inflammation was found at follow-up. In the future studies, details of occupational exposures, such as duration of exposures and cumulative exposures, need to be included to investigate the airborne occupational exposures and inflammatory biomarkers.

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

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 (PM2.5) 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 PM2.5 and BC was assessed. Lung function was measured by spirometry and Global Initiative (GLI) z-scores of forced expiratory volume in 1s (FEV1) 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 PM2.5 but not BC was related to higher CPT and slower cognitive processing speed [Total Effect PM2.5: FEV1 model = 8.31 × 10-3 (95% CI: 5.71 × 10-3, 10.91 × 10-3), FVC model = 8.30 × 10-3 (95% CI: 5.69 × 10-3, 10.90 × 10-3)]. The direct association of PM2.5 constituted more than 97% of the total effect. Mediation by lung function was low for PM2.5 with a mediated proportion of 1.32% (FEV1) 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 PM2.5 and BC, and cognitive performance. However, higher exposure to PM2.5 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.

Pre-conception and prenatal factors influencing gestational weight gain: a prospective study in Tigray region, northern Ethiopia.

BACKGROUND: In low-income countries, the high prevalence of pre-pregnancy undernutrition remains a challenge for the future health of women and their offspring. On top of good nutrition, adequate gestational weight gain has been recognized as an essential prerequisite for optimal maternal and child health outcomes. However, good-quality data on factors influencing gestational weight gain is lacking. Therefore, this study was aimed to prospectively identify pre-conception and prenatal factors influencing gestational weight gain in Ethiopia. METHODS: A population based prospective study was undertaken between February 2018 and January 2019 in the Tigray region, northern Ethiopia. Firstly, the weight of non-pregnant women of reproductive age living in the study area was measured between August and October 2017. Subsequently, eligible pregnant women identified during the study period were included consecutively and followed until birth. Data were collected through an interviewer-administered questionnaire and anthropometric measurements complemented with secondary data. Gestational weight gain, i.e., the difference between 32 to 36 weeks of gestation and pre-pregnancy weights, was classified as per the Institute of Medicine (IOM) guideline. Linear, spline, and logistic regression models were used to estimate the influence of pre-conception and prenatal factors on gestational weight gain. RESULTS: The mean gestational weight gain (standard deviation[SD]) was 10.6 (2.3) kg. Overall, 64.0% (95% CI 60.9, 67.1) of the women did not achieve adequate weight gain. Factors associated with higher gestational weight gain were higher women empowerment (B 0.60, 95% CI 0.06, 1.14), dietary diversity (B 0.39, 95% CI 0.03, 0.76), pre-pregnancy body mass index (B 0.13, 95% CI 0.05, 0.22), and haemoglobin (B 0.54, 95% CI 0.45, 0.64). Additionally, adequate prenatal care (B 0.58, 95% CI 0.28, 0.88) was associated with higher gestational weight gain. CONCLUSIONS: Adequate gestational weight gain was not achieved by most women in the study area, primarily not by those who were underweight before pregnancy. Interventions that advance women's empowerment, dietary quality, pre-pregnancy nutritional status, and prenatal care utilization may improve gestational weight gain and contribute to optimizing maternal and child health outcomes.