116 results found
The exposome concept refers to the totality of exposures from a variety of external and internal sources including chemical agents, biological agents, or radiation, from conception onward, over a complete lifetime. It encompasses also “psychosocial components” including the impact of social relations and socio-economic position on health. In this review we provide examples of recent contributions from exposome research, where we believe their application will be of the greatest value for moving forward. So far, environmental epidemiology has mainly focused on hard outcomes, such as mortality, disease exacerbation and hospitalizations. However, there are many subtle outcomes that can be related to environmental exposures, and investigations can be facilitated by an improved understanding of internal biomarkers of exposure and response, through the application of omic technologies. Second, though we have a wealth of studies on environmental pollutants, the assessment of causality is often difficult because of confounding, reverse causation and other uncertainties. Biomarkers and omic technologies may allow better causal attribution, for example using instrumental variables in triangulation, as we discuss here. Even more complex is the understanding of how social relationships (in particular socio-economic differences) influence health and imprint on the fundamental biology of the individual. The identification of molecular changes that are intermediate between social determinants and disease status is a way to fill the gap. Another field in which biomarkers and omics are relevant is the study of mixtures. Epidemiology often deals with complex mixtures (e.g. ambient air pollution, food, smoking) without fully disentangling the compositional complexity of the mixture, or with rudimentary approaches to reflect the overall effect of multiple exposures or components.From the point of view of disease mechanisms, most models hypothesize that several stages need t
Chadeau M, Alfano R, Ghantous A, et al., 2020, A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism, Metabolism: clinical and experimental, Vol: 110, Pages: 1-12, ISSN: 0026-0495
BackgroundBirthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.MethodsTo investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations.ResultsThis dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns.ConclusionsOur data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight.
Mancini FR, Laine JE, Tarallo S, et al., 2020, microRNA expression profiles and personal monitoring of exposure to particulate matter, Environmental Pollution, Vol: 263, ISSN: 0269-7491
An increasing number of findings from epidemiological studies support associations between exposure to air pollution and the onset of several diseases, including pulmonary, cardiovascular and neurodegenerative diseases, and malignancies. However, intermediate, and potentially mediating, biological mechanisms associated with exposure to air pollutants are largely unknown. Previous studies on the human exposome have shown that the expression of certain circulating microRNAs (miRNAs), regulators of gene expression, are altered upon exposure to traffic-related air pollutants. In the present study, we investigated the relationship between particulate matter (PM) smaller than 2.5 μm (PM2.5), PM2.5 absorbance (as a proxy of black carbon and soot), and ultrafine-particles (UFP, smaller than 0.1 μm), measured in healthy volunteers by 24 h personal monitoring (PEM) sessions and global expression levels of peripheral blood miRNAs. The PEM sessions were conducted in four European countries, namely Switzerland (Basel), United Kingdom (Norwich), Italy (Turin), and The Netherlands (Utrecht). miRNAs expression levels were analysed using microarray technology on blood samples from 143 participants. Seven miRNAs, hsa-miR-24-3p, hsa-miR-4454, hsa-miR-4763-3p, hsa-miR-425-5p, hsa-let-7d-5p, hsa-miR-502-5p, and hsa-miR-505-3p were significantly (FDR corrected) expressed in association with PM2.5 personal exposure, while no significant association was found between miRNA expression and the other pollutants. The results obtained from this investigation suggest that personal exposure to PM2.5 is associated with miRNA expression levels, showing the potential for these circulating miRNAs as novel biomarkers for air pollution health risk assessment.
Chadeau M, Bodinier B, Elliott J, et al., Risk factors for positive and negative COVID-19 tests: a cautious and in-depth analysis of UK Biobank data, International Journal of Epidemiology, ISSN: 0300-5771
BackgroundThe recent COVID-19 outbreak has generated an unprecedented public health crisis, with millions of infections and hundreds of thousands of deaths worldwide. Using hospital-based or mortality data, several COVID-19 risk factors have been identified, but these may be confounded or biased.MethodsUsing SARS-CoV-2 infection test data (N=4,509 tests; 1,325 positive) from Public Health England, linked to the UK Biobank study, we explored the contribution of demographic, social, health risk, medical, and environmental factors to COVID-19 risk. We used multivariable and penalised logistic regression models for the risk of (i) being tested, (ii) testing positive/negative in the study population and, adopting a test negative design, (iv) the risk of testing positive within the tested population.ResultsIn the fully adjusted model, variables independently associated with the risk of being tested for COVID-19 with OR >1.05 were: male sex; Black ethnicity; social disadvantage (as measured by education, housing and income); occupation (healthcare worker, retired, unemployed); ever smoker; severely obese; comorbidities; and greater exposure to PM2.5-absorbance. Of these, only male sex, non-White ethnicity, lower educational attainment, and none of the comorbidities or health risk factors, were associated with testing positive among tested individuals.ConclusionsWe adopted a careful and exhaustive approach within a large population-based cohort, which enabled us to triangulate evidence linking, male sex, lower educational attainment, non-White ethnicity with the risk of COVID-19. The elucidation of the joint and independent effects of these factors is a high-priority area for further research to inform on COVID-19 natural history.
Chadeau M, Petrovic D, Haba-Rubio J, et al., 2020, The contribution of sleep to social inequalities in cardiovascular disorders: a multi-cohort study, Cardiovascular Research, Vol: 116, Pages: 1514-1524, ISSN: 0008-6363
Aims: Sleep disturbances exhibit a strong social patterning, and inadequate sleep has been associated with adverse health outcomes, including cardiovascular disorders (CVD). However, the contribution of sleep to socioeconomic inequalities in CVD is unclear. This study pools data from eight European cohorts to investigate the role of sleep duration in the association between life-course socioeconomic status (SES) and CVD. Methods and Results We used cross-sectional data from eight European cohorts, totaling 111,205 participants. Life- course SES was assessed using father’s and adult occupational position. Self-reported sleep duration was categorized into recommended (6h-8.5h/night), long (>8.5h/night), and short (<6h/night). We examined two cardiovascular outcomes: coronary heart disease (CHD) and stroke. Main analyses were conducted using pooled data and examined the association between life-course SES and CVD, and the contribution of sleep duration to this gradient using counterfactual mediation. Low father’s occupational position was associated with an increased risk of CHD (men: OR=1.19, 95% CI [1.04;1.37]; women: OR=1.25, 95% CI 61 [1.02;1.54]), with marginal decrease of the gradient after accounting for adult occupational position (men: OR=1.17, 95% CI [1.02;1.35]; women: OR=1.22, 95% CI [0.99;1.52]), and no mediating effect by short sleep duration. Low adult occupational position was associated with an increased risk of CHD in both men and women (men: OR=1.48, 95% CI [1.14;1.92]; women: OR=1.53, 95% CI [1.04;2.21. Short sleep duration meaningfully contributed to the association between adult occupational position and CHD in men, with 13.4% mediation. Stroke did not exhibit a social patterning with any of the variables examined. Conclusion: This study suggests that inadequate sleep accounts to a meaningful proportion of the association between adult occupational position and coronary heart disease, at least in men. With slee
Appenzeller BMR, Chadeau-Hyam M, Aguilar L, 2020, Skin exposome science in practice : current evidence on hair biomonitoring and future perspectives., J Eur Acad Dermatol Venereol, Vol: 34 Suppl 4, Pages: 26-30
The skin exposome, defined as the totality of environmental exposures from conception to death that can induce or modify various skin conditions, compiles environmental, lifestyle and psychosocial exposures, as well as the resulting internal biological and physiological responses to these exposures. Biomonitoring can be used to obtain information on the internal dose of pollutants. The concentration of biomarkers in body fluids is highly variable over time due to differential elimination kinetics of chemicals, whereas they accumulate in hair. Hair analysis thus provides information on cumulative exposure over a longer period of time, and so can be used for assessing chronic exposure to pollutants. Studies on hair samples collected from 204 women living in two cities in China with different levels of pollution demonstrated that hair damage and the skin microbiome are biomarkers of a polluted city and long-term exposure to pollution and UV can increase signs of facial ageing. Adopting an exposome approach to skin health requires assessing multiple exposures and biological consequences, possibly in relation to longitudinally followed-up health outcomes. Leveraging "omics" data (e.g. metabolomics, proteomics, genomics and microbiome) and big data analytics, in particular multivariate analysis, will help to further understand the impact of pollution on skin and the combined effects with other exposome factors, including solar radiation and other environmental exposures.
Chadeau M, Castagne R, Kelly-Irving M, et al., A multi-omics approach to investigate the inflammatory response to life course socioeconomic position, Epigenomics, ISSN: 1750-1911
Aims: Inflammation represents a potential pathway through which socioeconomic position (SEP) is biologically embedded. Materials & Methods: We analysed inflammatory biomarkers in response to life course SEP by integrating multi-omics DNA-methylation, gene expression and protein level in 178 EPIC-Italy participants. Results & Conclusions: We identified 61 potential cis acting CpG loci whose methylation levels were associated with gene expression at a Bonferroni correction. We examined the relationships between life course SEP and these 61 cis-acting regulatory methylation sites (eMS) individually and jointly using several scores. Less advantaged SEP participants exhibit, later in life, a lower inflammatory methylome score, suggesting an overall increased expression of the corresponding inflammatory genes or proteins, supporting the hypothesis that SEP impacts adult physiology through inflammation.
Robinson O, Chadeau Hyam M, Karaman I, et al., 2020, Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort, Aging Cell, Vol: 19, Pages: 1-13, ISSN: 1474-9718
Markers of biological aging have potential utility in primary care and public health. We developed a model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography–mass spectrometry in urine and serum, within a large sample (N = 2,239) from the UK Airwave cohort. We validated a subset of model predictors in a Finnish cohort including repeat measurements from 2,144 individuals. We investigated the determinants of accelerated aging, including lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (mean r = .86 across independent test sets). Increased metabolomic age acceleration (mAA) was associated after false discovery rate (FDR) correction with overweight/obesity, diabetes, heavy alcohol use and depression. DNA methylation age acceleration measures were uncorrelated with mAA. Increased DNA methylation phenotypic age acceleration (N = 1,110) was associated after FDR correction with heavy alcohol use, hypertension and low income. In conclusion, metabolomics is a promising approach for the assessment of biological age and appears complementary to established epigenetic clocks.
Dagnino S, Bodinier B, Grigoryan H, et al., 2020, Agnostic Cys34-albumin adductomics and DNA methylation: implication of Nacetylcysteine in lung carcinogenesis years before diagnosis, International Journal of Cancer, Vol: 146, Pages: 3294-3303, ISSN: 0020-7136
Although smoking and oxidative stress are known contributors to lung carcinogenesis, theirmechanisms of action remain poorly understood. To shed light into these mechanisms, weapplied a novel approach using Cys34-adductomics in a lung cancer nested case-controlstudy (n=212). Adductomics profiles were integrated with DNA-methylation data atestablished smoking-related CpG sites measured in the same individuals. Our analysisidentified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant incases and controls: adduct of N-acetylcysteine (NAC, p=4.15x10-3) and of Cysteinyl-Glycine(Cys-Gly, p=7.89x10-3). Blood levels of the former were found associated to the methylationlevels at 11 smoking related CpG sites. We detect, for the first time in prospective bloodsamples, and irrespective of time-to-diagnosis, decreased levels of NAC adduct in lungcancer cases. Altogether, our results highlight the potential role of these adducts in theoxidative stress response contributing to lung carcinogenesis years before diagnosis.
Vineis P, Avendano-Pabon M, Barros H, et al., 2020, Special report: the biology of inequalities in health: the lifepath consortium, Frontiers in Public Health, Vol: 8, Pages: 1-37, ISSN: 2296-2565
Funded by the European Commission Horizon 2020 programme, the Lifepath research consortium aimed to investigate the effects of socioeconomic inequalities on the biology of healthy aging. The main research questions included the impact of inequalities on health, the role of behavioral and other risk factors, the underlying biological mechanisms, the efficacy of selected policies, and the general implications of our findings for theories and policies. The project adopted a life-course and comparative approach, considering lifetime effects from childhood and adulthood, and pooled data on up to 1.7 million participants of longitudinal cohort studies from Europe, USA, and Australia. These data showed that socioeconomic circumstances predicted mortality and functional decline as strongly as established risk factors currently targeted by global prevention programmes. Analyses also looked at socioeconomically patterned biological markers, allostatic load, and DNA methylation using richly phenotyped cohorts, unraveling their association with aging processes across the life-course. Lifepath studies suggest that socioeconomic circumstances are embedded in our biology from the outset—i.e., disadvantage influences biological systems from molecules to organs. Our findings have important implications for policy, suggesting that (a) intervening on unfavorable socioeconomic conditions is complementary and as important as targeting well-known risk factors, such as tobacco and alcohol consumption, low fruit and vegetable intake, obesity and a sedentary lifestyle, and that (b) effects of preventive interventions in early life integrate interventions in adulthood. The report has an executive summary that refers to the different sections of the main paper.
Laine JE, Baltar VT, Stringhini S, et al., 2020, Reducing socio-economic inequalities in all-cause mortality: a counterfactual mediation approach (vol 49, pg 497, 2020), INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 49, Pages: 707-707, ISSN: 0300-5771
Laine J, Baltar VT, Stringini S, et al., 2020, Reducing socioeconomic inequalities in all-cause mortality: a counterfactual mediation approach, International Journal of Epidemiology, Vol: 49, Pages: 497-510, ISSN: 0300-5771
Background: Socioeconomicinequalities inmortality arewell established, yet the contribution of intermediate risk factors that may underlie these relationships remains unclear.We evaluated the role of multiple modifiable intermediate risk factors underlyingsocioeconomicassociated-mortality and quantifiedthe potentialimpact of reducing early all-cause mortality by hypothetically altering socioeconomic risk factors. Methods: Data were fromsevencohort studies participating in the LIFEPATH consortium (total n=179,090). Using bothsocioeconomic position (SEP) (based on occupation) and education, we estimated thenaturaldirect effect on all-cause mortality, and thenatural indirect effect via the joint mediatingrole of smoking, alcohol intake, dietary patterns, physical activity, body mass index,hypertension, diabetes, and coronary artery disease.Hazard ratios(HR)were estimated, using counterfactual natural effect modelsunder different hypothetical actions of either lower or higher SEP or education. Results: Lower SEP and educationwereassociated with anincreaseinall-cause mortalitywithin an average follow up time of 17.5 years.Mortality wasreducedviamodelled hypothetical actions of increasing SEP oreducation. Through higher educationtheHR was0.85(95% confidence interval (CI) 0.84, 0.86) for women and 0.71(95% CI 0.70, 0.74)for men,compared to lower education. In addition, 34% and 38% of the effect was jointlymediatedfor womenand men, respectively. The benefits from alteringSEP were slightly more modest.Conclusions: Theseobservational findings supportpoliciesto reducemortalityboththrough improving socioeconomic circumstances and increasing education,andby altering intermediaries, such as lifestyle behaviours and morbidities.
Elliott J, Bodinier B, Bond TA, et al., 2020, Predictive Accuracy of a Polygenic Risk Score-Enhanced Prediction Model vs a Clinical Risk Score for Coronary Artery Disease, JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, Vol: 323, Pages: 636-645, ISSN: 0098-7484
Sanikini H, Muller DC, Sophiea M, et al., 2020, Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, International Journal of Cancer, Vol: 146, Pages: 929-942, ISSN: 0020-7136
Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow‐up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m2: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist‐to‐hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.
Preston GW, Dagnino S, Ponzi E, et al., 2020, Relationships between airborne pollutants, serum albumin adducts and short-term health outcomes in an experimental crossover study, Chemosphere, Vol: 239, ISSN: 1879-1298
Exposure to air pollution can have both short-term and long-term effects on health. However, the relationships between specific pollutants and their effects can be obscured by characteristics of both the pollution and the exposed population. One way of elucidating the relationships is to link exposures and internal changes at the level of the individual. To this end, we combined personal exposure monitoring (59 individuals, Oxford Street II crossover study) with mass-spectrometry-based analyses of putative serum albumin adducts (fixed-step selected reaction monitoring). We attempted to infer adducts' identities using data from another, higher-resolution mass spectrometry method, and were able to detect a semi-synthetic standard with both methods. A generalised least squares regression method was used to test for associations between amounts of adducts and pollution measures (ambient concentrations of nitrogen dioxide and particulate matter), and between amounts of adducts and short-term health outcomes (measures of lung health and arterial stiffness). Amounts of some putative adducts (e.g., one with a positive mass shift of approximately 143Da) were associated with exposure to pollution (11 associations), and amounts of other adducts were associated with health outcomes (eight associations). Adducts did not appear to provide a link between exposures and short-term health outcomes.
Bowden SJ, Kalliala I, Veroniki AA, et al., 2019, The use of Human Papillomavirus DNA Methylation in cervical intraepithelial neoplasia: a systematic review and meta-analysis, EBioMedicine, Vol: 50, Pages: 246-259, ISSN: 2352-3964
BackgroundMethylation of viral DNA has been proposed as a novel biomarker for triage of human papillomavirus(HPV) positive women at screening. This systematic review and meta-analysis aims to assess how methylation levels change with disease severity and to determine diagnostic test accuracy (DTA) in detectinghigh-grade cervical intra-epithelial neoplasia (CIN).MethodsWe performed searches in MEDLINE, EMBASE and CENTRAL from inception to October 2019. Studies were eligible if they explored HPV methylation levels in HPV positive women. Data were extracted induplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effectsbinary regression model were applied to determine pooled effect estimates.Findings44 studies with 8819 high-risk HPV positive women were eligible. The pooled estimates for positive methylation rate in HPV16 L1 gene were higher for high-grade CIN (≥CIN2/high-grade squamousintra-epithelial lesion (HSIL) (95% confidence interval (95%CI:72·7% (47·8–92·2))) vs. low-grade CIN(≤CIN1/low-grade squamous intra-epithelial lesion (LSIL) (44·4% (95%CI:16·0–74·1))). Pooled differencein mean methylation level was significantly higher in ≥CIN2/HSIL vs. ≤CIN1/LSIL for HPV16 L1 (11·3%(95%CI:6·5–16·1)). Pooled odds ratio of HPV16 L1 methylation was 5·5 (95%CI:3·5–8·5) for ≥CIN2/HSIL vs. ≤CIN1/LSIL (p < 0·0001). HPV16 L1/L2 genes performed best in predicting CIN2 or worse(pooled sensitivity 77% (95%CI:63–87), specificity 64% (95%CI:55–71), area under the curve (0·73(95%CI:0·69–0·77)).InterpretationHigher HPV methylation is associated with increased disease severity, whilst HPV16 L1/L2 genes demonstrated high diagnostic accuracy to detect high-grade CIN in HPV16 positive women. Direct clinical use islimited by the need for a multi-genotype and standardised ass
Bowden S, Kalliala I, Veroniki A, et al., 2019, THE USE OF HUMAN PAPILLOMAVIRUS DNA METHYLATION IN CERVICAL INTRAEPITHELIAL NEOPLASIA: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A84-A86, ISSN: 1048-891X
Chadeau-Hyam M, Karimi M, Castagne R, et al., 2019, A socially patterned Biological Health Score and mortality in Understanding Society and UKBiobank, Publisher: OXFORD UNIV PRESS, Pages: 89-89, ISSN: 1101-1262
Bowden S, Kalliala I, Wielscher M, et al., 2019, CERVICAL INTRAEPITHELIAL NEOPLASIA AND CERVICAL CANCER: A GENOME WIDE ASSOCIATION STUDY (GWAS) OF THE UK BIOBANK COHORT, Publisher: BMJ PUBLISHING GROUP, Pages: A59-A60, ISSN: 1048-891X
Castagne R, Chadeau-Hyam M, Karimi M, et al., 2019, Social patterning of inflammation over the lifecourse and its relationship with mortality, Publisher: OXFORD UNIV PRESS, ISSN: 1101-1262
Carmeli C, Kutalik Z, Kelly-Irving M, et al., 2019, Early life socioeconomic position and adult systemic inflammation: the role of gene regulation, Publisher: OXFORD UNIV PRESS, Pages: 88-88, ISSN: 1101-1262
Krauskopf J, van Veldhoven K, Chadeau-Hyam M, et al., 2019, Cell-free, circulating microRNAs reflect air pollution-induced environmental health risks, 55th Congress of the European-Societies-of-Toxicology (EUROTOX) - Toxicology - Science Providing Solutions, Publisher: ELSEVIER IRELAND LTD, Pages: S68-S68, ISSN: 0378-4274
Tzoulaki I, Castagné R, Boulangé CL, et al., 2019, Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease, European Heart Journal, Vol: 40, Pages: 2883-2896, ISSN: 1522-9645
Aims: To characterise serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). Methods and Results: We used untargeted one-dimensional (1D) serum metabolic profiling by proton (1H) nuclear magnetic resonance (NMR) spectroscopy among 3,867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3,569 participants from the Rotterdam and LOLIPOP Studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 NMR measured metabolites were associated with CAC and/or IMT, P =1.3x10-14 to 6.5x10-6 (discovery), P =4.2x10-14 to 4.4x10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched-chain and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide and lactate as well as apolipoprotein B (P <0.05). Conclusion: Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclero
Castagne R, Kelly-Irving M, Kyrtopoulos SA, et al., 2019, A MULTI-OMICS APPROACH TO INVESTIGATE THE INFLAMMATORY RESPONSE OF LIFE COURSE SOCIOECONOMIC POSITION: FINDINGS FROM EPIC-ITALY, Publisher: BMJ PUBLISHING GROUP, Pages: A40-A40, ISSN: 0143-005X
Karimi M, Castagne R, Delpierre C, et al., 2019, Early-life inequalities and biological ageing: A multi-system biological health score approach in the Understanding Society study, Journal of Epidemiology and Community Health, Vol: 73, Pages: 693-702, ISSN: 0143-005X
Social position is known to play a role in the quality of ageing, notably through the stimulation/dysregulation of key physiological systems in response to external stresses. Using data from one wave of the Understanding Society panel study including 9,088 participants, we defined, as an extension of the Allostatic Load, a synthetic biological health score (BHS) capturing the wear-and-tear of four physiological systems (endocrine, inflammatory, cardiovascular, and metabolic systems), and two organs (liver and kidney). We used 16 established blood-derived biomarkers of these systems to calculate the BHS and explored the relative contribution of socio-economic position to the BHS and its main components across age groups.We identified a systematic decreasing education-related gradient of the BHS (p<0.001) leading to lower biological risk in participants with longer education. Education-related differences in the BHS were detected early in life, and were not attributable to lifestyle and behavioural factors. We found a consistent contribution of the inflammatory and metabolic systems to the overall score throughout from early adulthood onwards, while the contribution of the other four systems seem to vary across age groups and gender. Our findings highlight the social-to-biological processes ultimately leading to health inequalities, and suggest that such disparities can already be detected in the 20-40 years old age group and cannot be fully explained by lifestyle and behavioural factors. This may define early adulthood social condition as a precursor to accelerated biological ageing and as an important target for public health policies.
Krauskopf J, van Veldhoven K, Chadeau-Hyam M, et al., 2019, Short-term exposure to traffic-related air pollution reveals a compound-specific circulating miRNA profile indicating multiple disease risks, Environment International, Vol: 128, Pages: 193-200, ISSN: 0160-4120
Traffic-related air pollution (TRAP) is a complex mixture of compounds that contributes to the pathogenesis of many diseases including several types of cancer, pulmonary, cardiovascular and neurodegenerative diseases, and more recently also diabetes mellitus. In search of an early diagnostic biomarker for improved environmental health risk assessment, recent human studies have shown that certain extracellular miRNAs are altered upon exposure to TRAP. Here, we present a global circulating miRNA analysis in a human population exposed to different levels of TRAP. The cross-over study, with sampling taking place during resting and physical activity in two different exposure scenarios, included for each subject personal exposure measurements of PM10,PM2.5, NO, NO2, CO, CO2, BC and UFP. Next-generation sequencing technology was used to identify global circulating miRNA levels across all subjects. We identified 8 miRNAs to be associated with the mixture of TRAP and 27 miRNAs that were associated with the individual pollutants NO, NO2, CO, CO2, BC and UFP. We did not find significant associations between miRNA levels and PM10 or PM2.5. Integrated network analysis revealed that these circulating miRNAs are potentially involved in processes that are implicated in the development of air pollution-induced diseases. Altogether, this study demonstrates that signatures consisting of circulating miRNAs present a potential novel biomarker to be used in health risk assessment.
McCrory C, Leahy S, Ribeiro AI, et al., 2019, Maternal educational inequalities in measured body mass index trajectories in three European countries, PAEDIATRIC AND PERINATAL EPIDEMIOLOGY, Vol: 33, Pages: 226-237, ISSN: 0269-5022
Fiorito G, McCrory C, Robinson O, et al., 2019, Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis, Aging, Vol: 11, Pages: 2045-2070, ISSN: 1945-4589
Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) hasbeen proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries. The four biological aging biomarkers were associated with education and different sets of risk factors independently,and themagnitude of the effectsdiffereddepending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception ofsmoking, which hada significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.
Reimann B, Janssen BG, Alfano R, et al., 2019, The cord blood insulin and mitochondrial DNA content related methylome, Frontiers in Genetics, Vol: 10, ISSN: 1664-8021
Mitochondrial dysfunction seems to play a key role in the etiology of insulin resistance. At birth, a link has already been established between mitochondrial DNA (mtDNA) content and insulin levels in cord blood. In this study, we explore shared epigenetic mechanisms of the association between mtDNA content and insulin levels, supporting the developmental origins of this link. First, the association between cord blood insulin and mtDNA content in 882 newborns of the ENVIRONAGE birth cohort was assessed. Cord blood mtDNA content was established via qPCR, while cord blood levels of insulin were determined using electrochemiluminescence immunoassays. Then the cord blood DNA methylome and transcriptome were determined in 179 newborns, using the human 450K methylation Illumina and Agilent Whole Human Genome 8 × 60 K microarrays, respectively. Subsequently, we performed an epigenome-wide association study (EWAS) adjusted for different maternal and neonatal variables. Afterward, we focused on the 20 strongest associations based on p-values to assign transcriptomic correlates and allocate corresponding pathways employing the R packages ReactomePA and RDAVIDWebService. On the regional level, we examined differential methylation using the DMRcate and Bumphunter packages in R. Cord blood mtDNA content and insulin were significantly correlated (r = 0.074, p = 0.028), still showing a trend after additional adjustment for maternal and neonatal variables (p = 0.062). We found an overlap of 33 pathways which were in common between the association with cord blood mtDNA content and insulin levels, including pathways of neurodevelopment, histone modification, cytochromes P450 (CYP)-metabolism, and biological aging. We further identified a DMR annotated to Repulsive Guidance Molecule BMP Co-Receptor A (RGMA) linked to cord blood insulin as well as mtDNA content. Metabolic variation in early life represented by neonatal insulin levels and mtDNA content might reflect or accommodate
Berger E, Castagne R, Chadeau M, et al., 2019, Multi-cohort study identifies social determinants of systemic inflammation over the life course, Nature Communications, Vol: 10, ISSN: 2041-1723
Chronic inflammation has been proposed as having a prominent role in the construction of social inequalities in health. Disentangling the effects of early life and adulthood social disadvantage on inflammation is key in elucidating biological mechanisms underlying socioeconomic disparities. Here we explore the relationship between socioeconomic position (SEP) across the life course and inflammation (as measured by CRP levels) in up to 23,008 participants from six European cohort studies from three countries conducted between 1958 and 2013. We find a consistent inverse association between SEP and CRP across cohorts, where participants with a less advantaged SEP have higher levels of inflammation. Educational attainment is most strongly related to inflammation, after adjusting for health behaviours, body mass index and later-in-life SEP. These findings suggest socioeconomic disadvantage in young adulthood is independently associated with later life inflammation calling for further studies of the pathways operating through educational processes.
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