Publications by authors named "Marc Chadeau-Hyam"

101 Publications

Predictive symptoms for COVID-19 in the community: REACT-1 study of over 1 million people.

PLoS Med 2021 09 28;18(9):e1003777. Epub 2021 Sep 28.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Background: Rapid detection, isolation, and contact tracing of community COVID-19 cases are essential measures to limit the community spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to identify a parsimonious set of symptoms that jointly predict COVID-19 and investigated whether predictive symptoms differ between the B.1.1.7 (Alpha) lineage (predominating as of April 2021 in the US, UK, and elsewhere) and wild type.

Methods And Findings: We obtained throat and nose swabs with valid SARS-CoV-2 PCR test results from 1,147,370 volunteers aged 5 years and above (6,450 positive cases) in the REal-time Assessment of Community Transmission-1 (REACT-1) study. This study involved repeated community-based random surveys of prevalence in England (study rounds 2 to 8, June 2020 to January 2021, response rates 22%-27%). Participants were asked about symptoms occurring in the week prior to testing. Viral genome sequencing was carried out for PCR-positive samples with N-gene cycle threshold value < 34 (N = 1,079) in round 8 (January 2021). In univariate analysis, all 26 surveyed symptoms were associated with PCR positivity compared with non-symptomatic people. Stability selection (1,000 penalized logistic regression models with 50% subsampling) among people reporting at least 1 symptom identified 7 symptoms as jointly and positively predictive of PCR positivity in rounds 2-7 (June to December 2020): loss or change of sense of smell, loss or change of sense of taste, fever, new persistent cough, chills, appetite loss, and muscle aches. The resulting model (rounds 2-7) predicted PCR positivity in round 8 with area under the curve (AUC) of 0.77. The same 7 symptoms were selected as jointly predictive of B.1.1.7 infection in round 8, although when comparing B.1.1.7 with wild type, new persistent cough and sore throat were more predictive of B.1.1.7 infection while loss or change of sense of smell was more predictive of the wild type. The main limitations of our study are (i) potential participation bias despite random sampling of named individuals from the National Health Service register and weighting designed to achieve a representative sample of the population of England and (ii) the necessary reliance on self-reported symptoms, which may be prone to recall bias and may therefore lead to biased estimates of symptom prevalence in England.

Conclusions: Where testing capacity is limited, it is important to use tests in the most efficient way possible. We identified a set of 7 symptoms that, when considered together, maximize detection of COVID-19 in the community, including infection with the B.1.1.7 lineage.
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http://dx.doi.org/10.1371/journal.pmed.1003777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478234PMC
September 2021

Developing the building blocks to elucidate the impact of the urban exposome on cardiometabolic-pulmonary disease: The EU EXPANSE project.

Environ Epidemiol 2021 Aug 1;5(4):e162. Epub 2021 Jul 1.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.

By 2030, more than 80% of Europe's population will live in an urban environment. The urban exposome, consisting of factors such as where we live and work, where and what we eat, our social network, and what chemical and physical hazards we are exposed to, provides important targets to improve population health. The EXPANSE (EXposome Powered tools for healthy living in urbAN SEttings) project will study the impact of the urban exposome on the major contributors to Europe's burden of disease: Cardio-Metabolic and Pulmonary Disease. EXPANSE will address one of the most pertinent questions for urban planners, policy makers, and European citizens: "How to maximize one's health in a modern urban environment?" EXPANSE will take the next step in exposome research by (1) bringing together exposome and health data of more than 55 million adult Europeans and OMICS information for more than 2 million Europeans; (2) perform personalized exposome assessment for 5,000 individuals in five urban regions; (3) applying ultra-high-resolution mass-spectrometry to screen for chemicals in 10,000 blood samples; (4) evaluating the evolution of the exposome and health through the life course; and (5) evaluating the impact of changes in the urban exposome on the burden of cardiometabolic and pulmonary disease. EXPANSE will translate its insights and innovations into research and dissemination tools that will be openly accessible via the EXPANSE toolbox. By applying innovative ethics-by-design throughout the project, the social and ethical acceptability of these tools will be safeguarded. EXPANSE is part of the European Human Exposome Network.
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http://dx.doi.org/10.1097/EE9.0000000000000162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367039PMC
August 2021

Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study.

Lancet Oncol 2021 04;22(4):548-557

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK. Electronic address:

Background: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls.

Methods: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer.

Findings: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10), and HLA-DQA1 (rs9272050; p=7·90 × 10). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer.

Interpretation: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions.

Funding: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.
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http://dx.doi.org/10.1016/S1470-2045(21)00028-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008734PMC
April 2021

COVID-19 mortality in the UK Biobank cohort: revisiting and evaluating risk factors.

Eur J Epidemiol 2021 Mar 15;36(3):299-309. Epub 2021 Feb 15.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Hospital, Norfolk Place, London, W21PG, UK.

Most studies of severe/fatal COVID-19 risk have used routine/hospitalisation data without detailed pre-morbid characterisation. Using the community-based UK Biobank cohort, we investigate risk factors for COVID-19 mortality in comparison with non-COVID-19 mortality. We investigated demographic, social (education, income, housing, employment), lifestyle (smoking, drinking, body mass index), biological (lipids, cystatin C, vitamin D), medical (comorbidities, medications) and environmental (air pollution) data from UK Biobank (N = 473,550) in relation to 459 COVID-19 and 2626 non-COVID-19 deaths to 21 September 2020. We used univariate, multivariable and penalised regression models. Age (OR = 2.76 [2.18-3.49] per S.D. [8.1 years], p = 2.6 × 10), male sex (OR = 1.47 [1.26-1.73], p = 1.3 × 10) and Black versus White ethnicity (OR = 1.21 [1.12-1.29], p = 3.0 × 10) were independently associated with and jointly explanatory of (area under receiver operating characteristic curve, AUC = 0.79) increased risk of COVID-19 mortality. In multivariable regression, alongside demographic covariates, being a healthcare worker, current smoker, having cardiovascular disease, hypertension, diabetes, autoimmune disease, and oral steroid use at enrolment were independently associated with COVID-19 mortality. Penalised regression models selected income, cardiovascular disease, hypertension, diabetes, cystatin C, and oral steroid use as jointly contributing to COVID-19 mortality risk; Black ethnicity, hypertension and oral steroid use contributed to COVID-19 but not non-COVID-19 mortality. Age, male sex and Black ethnicity, as well as comorbidities and oral steroid use at enrolment were associated with increased risk of COVID-19 death. Our results suggest that previously reported associations of COVID-19 mortality with body mass index, low vitamin D, air pollutants, renin-angiotensin-aldosterone system inhibitors may be explained by the aforementioned factors.
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http://dx.doi.org/10.1007/s10654-021-00722-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882869PMC
March 2021

Prospective Identification of Elevated Circulating CDCP1 in Patients Years before Onset of Lung Cancer.

Cancer Res 2021 Jul 11;81(13):3738-3748. Epub 2021 Feb 11.

MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611235PMC
July 2021

Gene regulation contributes to explain the impact of early life socioeconomic disadvantage on adult inflammatory levels in two cohort studies.

Sci Rep 2021 Feb 4;11(1):3100. Epub 2021 Feb 4.

Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.

Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.
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http://dx.doi.org/10.1038/s41598-021-82714-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862626PMC
February 2021

Education, biological ageing, all-cause and cause-specific mortality and morbidity: UK biobank cohort study.

EClinicalMedicine 2020 Dec 19;29-30:100658. Epub 2020 Nov 19.

Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, Netherlands.

Background: Socioeconomic position as measured by education may be embodied and affect the functioning of key physiological systems. Links between social disadvantage, its biological imprint, and cause-specific mortality and morbidity have not been investigated in large populations, and yet may point towards areas for public health interventions beyond targeting individual behaviours.

Methods: Using data from 366,748 UK Biobank participants with 13 biomarker measurements, we calculated a Biological Health Score (BHS, ranging from 0 to 1) capturing the level of functioning of five physiological systems. Associations between BHS and incidence of cardiovascular disease (CVD) and cancer, and mortality from all, CVD, cancer, and external causes were examined. We explored the role of education in these associations. Mendelian randomisation using genetic evidence was used to triangulate these findings.

Findings: An increase in BHS of 0.1 was associated with all-cause (HR = 1.14 [1.12-1.16] and 1.09 [1.07-1.12] in men and women respectively), cancer (HR = 1.11 [1.09-1.14] and 1.07 [1.04-1.10]) and CVD (HR = 1.25 [1.20-1.31] and 1.21 [1.11-1.31]) mortality, CVD incidence (HR = 1.15 [1.13-1.16] and 1.17 [1.15-1.19]). These associations survived adjustment for education, lifestyle-behaviours, body mass index (BMI), co-morbidities and medical treatments. Mendelian randomisation further supported the link between the BHS and CVD incidence (HR = 1.31 [1.21-1.42]). The BHS contributed to CVD incidence prediction (age-adjusted C-statistic = 0.58), other than through education and health behaviours.

Interpretation: The BHS captures features of the embodiment of education, health behaviours, and more proximal unknown factors which all complementarily contribute to all-cause, cancer and CVD morbidity and premature death.
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http://dx.doi.org/10.1016/j.eclinm.2020.100658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788440PMC
December 2020

Prenatal Exposure to Multiple Air Pollutants, Mediating Molecular Mechanisms, and Shifts in Birthweight.

Environ Sci Technol 2020 11 30;54(22):14502-14513. Epub 2020 Oct 30.

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, Imperial College London, London SW7 2BU, United Kingdom.

Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM, PM, nitrogen oxides, NO, NO, ultrafine particles (UFP), and oxidative potential (OP) of PM on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM, PM, NO, and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM, PM, and NO were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.
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http://dx.doi.org/10.1021/acs.est.0c02657DOI Listing
November 2020

Anthropometry, body fat composition and reproductive factors and risk of oesophageal and gastric cancer by subtype and subsite in the UK Biobank cohort.

PLoS One 2020 20;15(10):e0240413. Epub 2020 Oct 20.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Background: Obesity has been positively associated with upper gastrointestinal cancers, but prospective data by subtype/subsite are limited. Obesity influences hormonal factors, which may play a role in these cancers. We examined anthropometry, body fat and reproductive factors in relation to oesophageal and gastric cancer by subtype/subsite in the UK Biobank cohort.

Methods: Among 458,713 UK Biobank participants, 339 oesophageal adenocarcinomas, 124 oesophageal squamous cell carcinomas, 137 gastric cardia and 92 gastric non-cardia cancers were diagnosed during a mean of 6.5 years follow-up. Cox models estimated multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Body mass index (BMI), hip circumference, waist circumference, waist-to-hip ratio, waist-to-height ratio, total body fat and trunk fat were positively associated with oesophageal adenocarcinoma (highest vs lowest category: HR = 2.33, 95%-CI:1.65-3.28; HR = 1.56, 95%-CI:1.15-2.13; HR = 2.30, 95%-CI:1.47-3.57; HR = 1.71, 95%-CI:1.01-2.90; HR = 2.87, 95%-CI:1.88-4.38; HR = 1.96, 95%-CI:1.30-2.96; HR = 2.34, 95%-CI:1.70-3.22, respectively). Although there were no statistically significant associations in combined sex analyses, BMI (HR = 1.83, 95%-CI:1.00-3.37), waist circumference (HR = 2.21, 95%-CI:1.27-3.84) and waist-to-hip ratio (HR = 1.92, 95%-CI:1.11-3.29) were associated with gastric cardia cancer in men; however, mutual adjustment attenuated the associations for BMI and waist-to-hip ratio. For oesophageal squamous cell carcinoma, statistically significant inverse associations were observed among women for BMI, hip circumference, waist circumference, waist-to-height ratio, total body fat and trunk fat, although they were based on small numbers. In addition, older age at first (HR = 0.44, 95%-CI:0.22-0.88) and last live birth (HR = 0.44, 95%-CI:0.22-0.87) were inversely associated with oesophageal squamous cell carcinoma and having a stillbirth/miscarriage/termination was positively associated (HR = 1.84, 95%-CI:1.10-3.07).

Conclusions: Obesity and abdominal obesity specifically may be a risk factor for oesophageal adenocarcinoma and gastric cardia cancer in men. Some reproductive factors may be associated with oesophageal squamous cell carcinoma in women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575071PMC
December 2020

Patterning of educational attainment across inflammatory markers: Findings from a multi-cohort study.

Brain Behav Immun 2020 11 10;90:303-310. Epub 2020 Sep 10.

UMR1027, Université de Toulouse, UPS, Inserm, Toulouse, France. Electronic address:

Background: Evidence suggests that the inflammatory reaction, an adaptive response triggered by a variety of harmful stimuli and conditions involved in the risk and development of many chronic diseases, is a potential pathway through which the socioeconomic environment is biologically embedded. Difficulty in interpreting the role of the inflammatory system in the embodiment dynamic arises because of heterogeneity across studies that use a limited but varied number of inflammatory markers. There is no consensus in the literature as to which inflammatory markers beyond the C-reactive protein and to a lesser extent interleukin 6 are related to the social environment. Accordingly, we aimed to investigate the association between educational attainment, and several markers of inflammation - C-reactive protein, fibrinogen, interleukin 6, interleukin 1β and tumor necrosis factor α- in 6 European cohort studies.

Methods: Up to 17,470 participants from six European cohort studies with data on educational attainment, health behaviors and lifestyle factors, and at least two different inflammatory markers. Four sub-datasets were drawn with varying numbers of participants to allow pairwise comparison of the social patterning of C-reactive protein and any other inflammatory markers. To evaluate within each sub-dataset the importance of the context and cohort specificities, linear regression-based analyses were performed separately for each cohort and combined in a random effect meta-analysis to determine the relationship between educational attainment and inflammation.

Results: We found that the magnitude of the relationship between educational attainment and five inflammatory biomarkers (C-reactive protein, fibrinogen, interleukin 6 and 1β and tumor necrosis factor α) was variable. By far the most socially patterned biomarker was C-reactive protein, followed by fibrinogen and to lesser extent interleukin 6, where a low educational attainment was associated with higher inflammation even after adjusting for health behaviours and body mass index. No association was found with interleukin 1β and tumor necrosis factor α.

Conclusions: Our study suggests different educational patterning of inflammatory biomarkers. Further large-scale research is needed to explore social differences in the inflammatory cascade in greater detail and the extent to which these differences contribute to social inequalities in health.
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http://dx.doi.org/10.1016/j.bbi.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140486PMC
November 2020

Cancer Loyalty Card Study (CLOCS): protocol for an observational case-control study focusing on the patient interval in ovarian cancer diagnosis.

BMJ Open 2020 09 8;10(9):e037459. Epub 2020 Sep 8.

Surgery and Cancer, Imperial College London, London, UK

Introduction: Ovarian cancer is the eighth most common cancer in women worldwide, and about 1 in 5 women with ovarian cancer do not receive treatment, because they are too unwell by the time they are diagnosed. Symptoms of ovarian cancer are non-specific or can be associated with other common conditions, and women experiencing these symptoms have been shown to self-manage them using over-the-counter medication. Results from a recent proof-of-concept study suggest there may be an increase in the purchases of painkillers and indigestion medication 10-12 months before ovarian cancer diagnosis. We propose a case-control study, as part of a larger project called the Cancer Loyalty Card Study (CLOCS), to investigate whether a significant change in medication purchases could be an indication for early signs of ovarian cancer, using data already collected through store loyalty cards.

Methods And Analysis: Using a retrospective case-control design, we aim to recruit 500 women diagnosed with ovarian cancer (cases) and 500 women without ovarian cancer (controls) in the UK who hold a loyalty card with at least one participating high street retailer. We will use pre-existing loyalty card data to compare past purchase patterns of cases with those of controls. In order to assess ovarian cancer risk in participants and their purchase patterns, we will collect information from participants on ovarian cancer risk factors and clinical data including symptoms experienced before diagnosis from recruited women with ovarian cancer.

Ethics And Dissemination: CLOCS was reviewed and approved by the North West-Greater Manchester South Research Ethics Committee (19/NW/0427). Study outcomes will be disseminated through academic publications, the study website, social media and a report to the research sites that support the study once results are published.

Trial Registration Number: ISRCTN 14897082, CPMS 43323, NCT03994653.
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http://dx.doi.org/10.1136/bmjopen-2020-037459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484869PMC
September 2020

A multi-omics approach to investigate the inflammatory response to life course socioeconomic position.

Epigenomics 2020 08 2;12(15):1287-1302. Epub 2020 Sep 2.

LEASP, UMR 1027, Inserm-Université Toulouse III Paul Sabatier, Toulouse, France.

Inflammation represents a potential pathway through which socioeconomic position (SEP) is biologically embedded. We analyzed inflammatory biomarkers in response to life course SEP by integrating multi-omics DNA-methylation, gene expression and protein level in 178 European Prospective Investigation into Cancer and Nutrition-Italy participants. We identified 61 potential 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 -acting regulatory methylation sites 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.
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http://dx.doi.org/10.2217/epi-2019-0261DOI Listing
August 2020

Risk factors for positive and negative COVID-19 tests: a cautious and in-depth analysis of UK biobank data.

Int J Epidemiol 2020 10;49(5):1454-1467

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Background: The 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.

Methods: Using SARS-CoV-2 infection test data (n = 4509 tests; 1325 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 penalized logistic regression models for the risk of (i) being tested, (ii) testing positive/negative in the study population and, adopting a test negative design, (iii) the risk of testing positive within the tested population.

Results: In the fully adjusted model, variables independently associated with the risk of being tested for COVID-19 with odds ratio >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 particulate matter (PM) 2.5 absorbance. Of these, only male sex, non-White ethnicity and lower educational attainment, and none of the comorbidities or health risk factors, were associated with testing positive among tested individuals.

Conclusions: We adopted a careful and exhaustive approach within a large population-based cohort, which enabled us to triangulate evidence linking male sex, lower educational attainment and 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 the natural history of COVID-19.
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http://dx.doi.org/10.1093/ije/dyaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454561PMC
October 2020

What is new in the exposome?

Environ Int 2020 10 30;143:105887. Epub 2020 Jun 30.

MRC Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, W2 1PG London, UK.

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 to be transitioned through health to the induction of disease, but very little is known about the characteristics and temporal sequence of such stages. Exposome models reinforce the idea of a biography-to-biology transition, in that everyone's disease is the product of the individual history of exposures, superimposed on their underlying genetic susceptibilities. Finally, exposome research is facilitated by technological developments that complement traditional epidemiological study designs. We describe in depth one such new tools, adductomics. In general, the development of high-resolution and high-throughput technologies interrogating multiple -omics (such as epigenomics, transcriptomics, proteomics, adductomics and metabolomics) yields an unprecedented perspective into the impact of the environment in its widest sense on disease. The world of the exposome is rapidly evolving, though a huge gap still needs to be filled between the original expectations and the concrete achievements. Perhaps the most urgent need is for the establishment of a new generation of cohort studies with appropriately specified biosample collection, improved questionnaire data (including social variables), and the deployment of novel technologies that allow better characterization of individual environmental exposures, ranging from personal monitoring to satellite based observations.
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http://dx.doi.org/10.1016/j.envint.2020.105887DOI Listing
October 2020

A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.

Metabolism 2020 09 15;110:154292. Epub 2020 Jun 15.

Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, United Kingdom; Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium. Electronic address:

Background: Birthweight 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.

Methods: To 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.

Results: This 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.

Conclusions: Our 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.
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http://dx.doi.org/10.1016/j.metabol.2020.154292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450273PMC
September 2020

Special Report: The Biology of Inequalities in Health: The Lifepath Consortium.

Front Public Health 2020 12;8:118. Epub 2020 May 12.

Unit of Population Epidemiology, Division of Primary Care, Geneva University Hospitals, Geneva, Switzerland.

Funded by the European Commission Horizon 2020 programme, the 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. 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.
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http://dx.doi.org/10.3389/fpubh.2020.00118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235337PMC
May 2021

Determinants of accelerated metabolomic and epigenetic aging in a UK cohort.

Aging Cell 2020 06 3;19(6):e13149. Epub 2020 May 3.

MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1111/acel.13149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294785PMC
June 2020

microRNA expression profiles and personal monitoring of exposure to particulate matter.

Environ Pollut 2020 Aug 18;263(Pt B):114392. Epub 2020 Mar 18.

Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, 10060 Candiolo, Turin, Italy. Electronic address:

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 (PM), PM 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 PM 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 PM is associated with miRNA expression levels, showing the potential for these circulating miRNAs as novel biomarkers for air pollution health risk assessment.
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http://dx.doi.org/10.1016/j.envpol.2020.114392DOI Listing
August 2020

Predictive Accuracy of a Polygenic Risk Score-Enhanced Prediction Model vs a Clinical Risk Score for Coronary Artery Disease.

JAMA 2020 02;323(7):636-645

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Importance: The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain.

Objective: To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations.

Design, Setting, And Participants: Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency-matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD.

Exposures: Polygenic risk score for CAD, pooled cohort equations, and both combined.

Main Outcomes And Measures: CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed.

Results: In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and -0.4% (95% CI, -0.5% to -0.4%) for noncases (overall net reclassification improvement, 4.0% [95% CI, 3.1% to 4.9%]).

Conclusions And Relevance: The addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.
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http://dx.doi.org/10.1001/jama.2019.22241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042853PMC
February 2020

Reducing socio-economic inequalities in all-cause mortality: a counterfactual mediation approach.

Int J Epidemiol 2020 04;49(2):497-510

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

Background: Socio-economic inequalities in mortality are well 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 underlying socio-economic-associated mortality and quantified the potential impact of reducing early all-cause mortality by hypothetically altering socio-economic risk factors.

Methods: Data were from seven cohort studies participating in the LIFEPATH Consortium (total n = 179 090). Using both socio-economic position (SEP) (based on occupation) and education, we estimated the natural direct effect on all-cause mortality and the natural indirect effect via the joint mediating role of smoking, alcohol intake, dietary patterns, physical activity, body mass index, hypertension, diabetes and coronary artery disease. Hazard ratios (HRs) were estimated, using counterfactual natural effect models under different hypothetical actions of either lower or higher SEP or education.

Results: Lower SEP and education were associated with an increase in all-cause mortality within an average follow-up time of 17.5 years. Mortality was reduced via modelled hypothetical actions of increasing SEP or education. Through higher education, the HR was 0.85 [95% confidence interval (CI) 0.84, 0.86] for women and 0.71 (95% CI 0.70, 0.74) for men, compared with lower education. In addition, 34% and 38% of the effect was jointly mediated for women and men, respectively. The benefits from altering SEP were slightly more modest.

Conclusions: These observational findings support policies to reduce mortality both through improving socio-economic circumstances and increasing education, and by altering intermediaries, such as lifestyle behaviours and morbidities.
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http://dx.doi.org/10.1093/ije/dyz248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266549PMC
April 2020

The contribution of sleep to social inequalities in cardiovascular disorders: a multi-cohort study.

Cardiovasc Res 2020 07;116(8):1514-1524

Centre universitaire de médecine Générale et santé publique (UNISANTÉ), Institute of Social and Preventive Medicine (IUMSP), Route de la Corniche 10, 1010 Lausanne, Switzerland.

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, totalling 111 205 participants. Life-course SES was assessed using father's and adult occupational position. Self-reported sleep duration was categorized into recommended (6-8.5 h/night), long (>8.5 h/night), and short (<6 h/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 [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 CHD, at least in men. With sleep increasingly being considered an important cardiovascular risk factor in its own terms, our study additionally points to its potential role in social inequalities in cardiovascular disease.
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http://dx.doi.org/10.1093/cvr/cvz267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425783PMC
July 2020

The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: A systematic review and meta-analysis.

EBioMedicine 2019 Dec 12;50:246-259. Epub 2019 Nov 12.

Department of Surgery and Cancer, 3rd Floor IRDB, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 ONN, London, UK; West London Gynaecology Cancer Centre, Hammersmith Hospital, Imperial Healthcare NHS Trust, UK. Electronic address:

Background: Methylation 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 detecting high-grade cervical intra-epithelial neoplasia (CIN).

Methods: We 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 in duplicate and requested from authors where necessary. Random-effects models and a bivariate mixed-effects binary regression model were applied to determine pooled effect estimates.

Findings: 44 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 squamous intra-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 difference in 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)).

Interpretation: Higher 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 is limited by the need for a multi-genotype and standardised assays. Next-generation multiplex HPV sequencing assays are under development and allow potential for rapid, automated and low-cost methylation testing.

Funding: NIHR, Genesis Research Trust, Imperial Healthcare Charity, Wellcome Trust NIHR Imperial BRC, European Union's Horizon 2020.
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http://dx.doi.org/10.1016/j.ebiom.2019.10.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921230PMC
December 2019

Agnostic Cys34-albumin adductomics and DNA methylation: Implication of N-acetylcysteine in lung carcinogenesis years before diagnosis.

Int J Cancer 2020 06 31;146(12):3294-3303. Epub 2019 Oct 31.

MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom.

Although smoking and oxidative stress are known contributors to lung carcinogenesis, their mechanisms of action remain poorly understood. To shed light into these mechanisms, we applied a novel approach using Cys34-adductomics in a lung cancer nested case-control study (n = 212). Adductomics profiles were integrated with DNA-methylation data at established smoking-related CpG sites measured in the same individuals. Our analysis identified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant in cases and controls: adduct of N-acetylcysteine (NAC, p = 4.15 × 10 ) and of cysteinyl-glycine (p = 7.89 × 10 ). Blood levels of the former were found associated to the methylation levels at 11 smoking-related CpG sites. We detect, for the first time in prospective blood samples, and irrespective of time to diagnosis, decreased levels of NAC adduct in lung cancer cases. Altogether, our results highlight the potential role of these adducts in the oxidative stress response contributing to lung carcinogenesis years before diagnosis.
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http://dx.doi.org/10.1002/ijc.32680DOI Listing
June 2020

Relationships between airborne pollutants, serum albumin adducts and short-term health outcomes in an experimental crossover study.

Chemosphere 2020 Jan 24;239:124667. Epub 2019 Aug 24.

MRC-PHE Centre for Environment & Health, Department of Analytical, Environmental & Forensic Sciences, School of Population Health & Environmental Sciences, Faculty of Life Sciences & Medicine, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. Electronic address:

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 ∼143 Da) 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.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124667DOI Listing
January 2020

Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease.

Eur Heart J 2019 09;40(34):2883-2896

Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.

Aims: To characterize 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 nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 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 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (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 atherosclerosis.
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http://dx.doi.org/10.1093/eurheartj/ehz235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963131PMC
September 2019

Short-term exposure to traffic-related air pollution reveals a compound-specific circulating miRNA profile indicating multiple disease risks.

Environ Int 2019 07 3;128:193-200. Epub 2019 May 3.

Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.

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 PM,PM, NO, NO, CO, CO, 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, NO, CO, CO, BC and UFP. We did not find significant associations between miRNA levels and PM or PM. 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.
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http://dx.doi.org/10.1016/j.envint.2019.04.063DOI Listing
July 2019

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.

Int J Cancer 2020 02 21;146(4):929-942. Epub 2019 May 21.

Institution of Clinical Sciences Malmö, Skåne University Hospital, Lund University, Sweden.

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/m : 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.
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http://dx.doi.org/10.1002/ijc.32386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973006PMC
February 2020

The Cord Blood Insulin and Mitochondrial DNA Content Related Methylome.

Front Genet 2019 12;10:325. Epub 2019 Apr 12.

Centre for Environmental Sciences, University of Hasselt, Hasselt, Belgium.

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 ENVIRAGE 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 -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 ( = 0.074, = 0.028), still showing a trend after additional adjustment for maternal and neonatal variables ( = 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 () 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 alterations in neurodevelopment, histone modification, CYP-metabolism, and aging, indicating etiological origins in epigenetic programming. Variation in metabolic hormones at birth, reflected by molecular changes, might via these alterations predispose children to metabolic diseases later in life. The results of this study may provide important markers for following targeted studies.
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http://dx.doi.org/10.3389/fgene.2019.00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474284PMC
April 2019

Early-life inequalities and biological ageing: a multisystem Biological Health Score approach in .

J Epidemiol Community Health 2019 08 3;73(8):693-702. Epub 2019 Apr 3.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

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 including 9088 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 socioeconomic 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 seems 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.
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http://dx.doi.org/10.1136/jech-2018-212010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678052PMC
August 2019
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