Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study.

BACKGROUND: Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated with an increased risk of developing such hallmark-related diseases. METHODS: In this multicohort study, we included people aged 38-72 years with data on weight, height, and waist circumference measured during a clinical examination at baseline between March 13, 2006, and Oct 1, 2010, from the UK Biobank with follow-up until Nov 12, 2021. To test reproducibility of the findings (replication analysis), we used data from people aged 40 years or older included in the Finnish Public Sector study and the Finnish Health and Social Support study who responded to the study surveys, had data on BMI, and were successfully linked to electronic health records from national registers up to Dec 31, 2016. Obesity and clinical characteristics were assessed at baseline. Via linkage to national health records, participants were followed up for 83 diseases related to nine ageing hallmarks (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication). Outcomes were the first instance of hallmark-related disease, in addition to co-occurrence of three or more hallmark-related diseases and mortality. FINDINGS: 496 530 adults (mean age 57·0 years [SD 8·1]) from the UK Biobank were included in the primary analysis, and 83 249 (mean age 48·2 years [6·4]) adults from the Finnish cohorts were included in the replication analysis. Median follow-up was 12·7 years (IQR 12·0-13·4) in the UK Biobank and 14·0 years (8·0-15·0) in the Finnish cohorts. After adjusting for demographic characteristics, lifestyle factors, and depression, UK Biobank participants with obesity (BMI ≥30·0 kg/m2) had a 1·40 (95% CI 1·38-1·41) times higher hazard ratio for the first hallmark-related disease than those with a healthy weight (BMI 18·5-24·9 kg/m2). The corresponding hazard ratios for three co-occurring diseases were 2·92 (95% CI 2·64-3·22) for deregulated nutrient sensing, 2·73 (2·46-3·02) for telomere attrition, 2·33 (2·10-2·60) for epigenetic alterations, 2·30 (2·14-2·48) for mitochondrial dysfunction, 2·23 (2·04-2·45) for stem cell exhaustion, 2·02 (1·89-2·16) for altered intercellular communication, 2·01 (1·89-2·15) for cellular senescence, 1·83 (1·67-2·00) for loss of proteostasis, and 1·39 (1·27-1·52) for genomic instability. These findings were replicated in the Finnish cohorts. In both studies, the associations between other risk factors (low education, unhealthy dietary factors [available only in the UK Biobank], smoking, high alcohol consumption, physical inactivity, and depression) and hallmark-related diseases were weaker than those with obesity. 45-60% of the excess mortality in people with obesity was attributable to hallmark-related diseases. INTERPRETATION: Obesity might have an important role in the development of diseases associated with cellular ageing. Tackling ageing mechanisms could potentially help to reduce the disease and mortality burden resulting from the obesity epidemic. FUNDING: Wellcome Trust, UK Medical Research Council, US National Institute on Aging, Academy of Finland, and Finnish Foundation for Cardiovascular Research. TRANSLATIONS: For the German and Finnish translations of the abstract see Supplementary Materials section.

Predicting work disability among people with chronic conditions: a prospective cohort study.

Few risk prediction scores are available to identify people at increased risk of work disability, particularly for those with an existing morbidity. We examined the predictive performance of disability risk scores for employees with chronic disease. We used prospective data from 88,521 employed participants (mean age 43.1) in the Finnish Public Sector Study including people with chronic disorders: musculoskeletal disorder, depression, migraine, respiratory disease, hypertension, cancer, coronary heart disease, diabetes, comorbid depression and cardiometabolic disease. A total of 105 predictors were assessed at baseline. During a mean follow-up of 8.6 years, 6836 (7.7%) participants were granted a disability pension. C-statistics for the 8-item Finnish Institute of Occupational Health (FIOH) risk score, comprising age, self-rated health, number of sickness absences, socioeconomic position, number of chronic illnesses, sleep problems, BMI, and smoking at baseline, exceeded 0.72 for all disease groups and was 0.80 (95% CI 0.80-0.81) for participants with musculoskeletal disorders, 0.83 (0.82-0.84) for those with migraine, and 0.82 (0.81-0.83) for individuals with respiratory disease. Predictive performance was not significantly improved in models with re-estimated coefficients or a new set of predictors. These findings suggest that the 8-item FIOH work disability risk score may serve as a scalable screening tool in identifying individuals with increased risk for work disability.

Association of alcohol use with years lived without major chronic diseases: A multicohort study from the IPD-Work consortium and UK Biobank.

Background: Heavy alcohol consumption increases the risk of several chronic diseases. In this multicohort study, we estimated the number of life-years without major chronic diseases according to different characteristics of alcohol use. Methods: In primary analysis, we pooled individual-level data from up to 129,942 adults across 12 cohort studies with baseline data collection on alcohol consumption, drinking patterns, and history between 1986 and 2005 (the IPD-Work Consortium). Self-reported alcohol consumption was categorised according to UK guidelines - non-drinking (never or former drinkers); moderate consumption (1-14 units); heavy consumption (>14 units per week). We further subdivided moderate and heavy drinkers by binge drinking pattern (alcohol-induced loss of consciousness). In addition, we assessed problem drinking using linked data on hospitalisations due to alcohol abuse or poisoning. Follow-up for chronic diseases for all participants included incident type 2 diabetes, coronary heart disease, stroke, cancer, and respiratory disease (asthma and chronic obstructive pulmonary disease) as ascertained via linkage to national morbidity and mortality registries, repeated medical examinations, and/or self-report. We estimated years lived without any of these diseases between 40 and 75 years of age according to sex and characteristics of alcohol use. We repeated the main analyses using data from 427,621 participants in the UK Biobank cohort study. Findings: During 1·73 million person-years at risk, 22,676 participants in IPD-Work cohorts developed at least one chronic condition. From age 40 to 75 years, never-drinkers [men: 29·3 (95%CI 27·9-30·8) years, women 29·8 (29·2-30·4) years)] and moderate drinkers with no binge drinking habit [men 28·7 (28·4-29·0) years, women 29·6 (29·4-29·7) years] had the longest disease-free life span. A much shorter disease-free life span was apparent in participants who experienced alcohol poisoning [men 23·4 (20·9-26·0) years, women 24·0 (21·4-26·5) years] and those with self-reported heavy overall consumption and binge drinking [men: 26·0 (25·3-26·8), women 27·5 (26·4-28·5) years]. The pattern of results for alcohol poisoning and self-reported alcohol consumption was similar in UK Biobank. In IPD-Work and UK Biobank, differences in disease-free years between self-reported moderate drinkers and heavy drinkers were 1·5 years or less. Interpretation: Individuals with alcohol poisonings or heavy self-reported overall consumption combined with a binge drinking habit have a marked 3- to 6-year loss in healthy longevity. Differences in disease-free life between categories of self-reported weekly alcohol consumption were smaller. Funding: Medical Research Council, National Institute on Aging, NordForsk, Academy of Finland, Finnish Work Environment Fund.

Work stress and loss of years lived without chronic disease: an 18-year follow-up of 1.5 million employees in Denmark.

We aimed to examine the association between exposure to work stress and chronic disease incidence and loss of chronic disease-free life years in the Danish workforce. The study population included 1,592,491 employees, aged 30-59 in 2000 and without prevalent chronic diseases. We assessed work stress as the combination of job strain and effort-reward imbalance using job exposure matrices. We used Cox regressions to estimate risk of incident hospital-diagnoses or death of chronic diseases (i.e., type 2 diabetes, coronary heart disease, stroke, cancer, asthma, chronic obstructive pulmonary disease, heart failure, and dementia) during 18 years of follow-up and calculated corresponding chronic disease-free life expectancy from age 30 to age 75. Individuals working in occupations with high prevalence of work stress had a higher risk of incident chronic disease compared to those in occupations with low prevalence of work stress (women: HR 1.04 (95% CI 1.02-1.05), men: HR 1.12 (95% CI 1.11-1.14)). The corresponding loss in chronic disease-free life expectancy was 0.25 (95% CI - 0.10 to 0.60) and 0.84 (95% CI 0.56-1.11) years in women and men, respectively. Additional adjustment for health behaviours attenuated these associations among men. We conclude that men working in high-stress occupations have a small loss of years lived without chronic disease compared to men working in low-stress occupations. This finding appeared to be partially attributable to harmful health behaviours. In women, high work stress indicated a very small and statistically non-significant loss of years lived without chronic disease.

Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies.

OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted ß -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted ß -0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted ß -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms.

Long-term risk of dementia following hospitalization due to physical diseases: A multicohort study.

INTRODUCTION: Conventional risk factors targeted by prevention (e.g., low education, smoking, and obesity) are associated with a 1.2- to 2-fold increased risk of dementia. It is unclear whether having a physical disease is an equally important risk factor for dementia. METHODS: In this exploratory multicohort study of 283,414 community-dwelling participants, we examined 22 common hospital-treated physical diseases as risk factors for dementia. RESULTS: During a median follow-up of 19 years, a total of 3416 participants developed dementia. Those who had erysipelas (hazard ratio = 1.82; 95% confidence interval = 1.53 to 2.17), hypothyroidism (1.94; 1.59 to 2.38), myocardial infarction (1.41; 1.20 to 1.64), ischemic heart disease (1.32; 1.18 to 1.49), cerebral infarction (2.44; 2.14 to 2.77), duodenal ulcers (1.88; 1.42 to 2.49), gastritis and duodenitis (1.82; 1.46 to 2.27), or osteoporosis (2.38; 1.75 to 3.23) were at a significantly increased risk of dementia. These associations were not explained by conventional risk factors or reverse causation. DISCUSSION: In addition to conventional risk factors, several physical diseases may increase the long-term risk of dementia.

Association of Healthy Lifestyle With Years Lived Without Major Chronic Diseases.

Importance: It is well established that selected lifestyle factors are individually associated with lower risk of chronic diseases, but how combinations of these factors are associated with disease-free life-years is unknown. Objective: To estimate the association between healthy lifestyle and the number of disease-free life-years. Design, Setting, and Participants: A prospective multicohort study, including 12 European studies as part of the Individual-Participant-Data Meta-analysis in Working Populations Consortium, was performed. Participants included 116 043 people free of major noncommunicable disease at baseline from August 7, 1991, to May 31, 2006. Data analysis was conducted from May 22, 2018, to January 21, 2020. Exposures: Four baseline lifestyle factors (smoking, body mass index, physical activity, and alcohol consumption) were each allocated a score based on risk status: optimal (2 points), intermediate (1 point), or poor (0 points) resulting in an aggregated lifestyle score ranging from 0 (worst) to 8 (best). Sixteen lifestyle profiles were constructed from combinations of these risk factors. Main Outcomes and Measures: The number of years between ages 40 and 75 years without chronic disease, including type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease. Results: Of the 116 043 people included in the analysis, the mean (SD) age was 43.7 (10.1) years and 70 911 were women (61.1%). During 1.45 million person-years at risk (mean follow-up, 12.5 years; range, 4.9-18.6 years), 17 383 participants developed at least 1 chronic disease. There was a linear association between overall healthy lifestyle score and the number of disease-free years, such that a 1-point improvement in the score was associated with an increase of 0.96 (95% CI, 0.83-1.08) disease-free years in men and 0.89 (95% CI, 0.75-1.02) years in women. Comparing the best lifestyle score with the worst lifestyle score was associated with 9.9 (95% CI 6.7-13.1) additional years without chronic diseases in men and 9.4 (95% CI 5.4-13.3) additional years in women (P < .001 for dose-response). All of the 4 lifestyle profiles that were associated with the highest number of disease-free years included a body-mass index less than 25 (calculated as weight in kilograms divided by height in meters squared) and at least 2 of the following factors: never smoking, physical activity, and moderate alcohol consumption. Participants with 1 of these lifestyle profiles reached age 70.3 (95% CI, 69.9-70.8) to 71.4 (95% CI, 70.9-72.0) years disease free depending on the profile and sex. Conclusions and Relevance: In this multicohort analysis, various healthy lifestyle profiles appeared to be associated with gains in life-years without major chronic diseases.

Job Strain as a Risk Factor for Peripheral Artery Disease: A Multi-Cohort Study.

Background Job strain is implicated in many atherosclerotic diseases, but its role in peripheral artery disease (PAD) is unclear. We investigated the association of job strain with hospital records of PAD, using individual-level data from 11 prospective cohort studies from Finland, Sweden, Denmark, and the United Kingdom. Methods and Results Job strain (high demands and low control at work) was self-reported at baseline (1985-2008). PAD records were ascertained from national hospitalization data. We used Cox regression to examine the associations of job strain with PAD in each study, and combined the study-specific estimates in random effects meta-analyses. We used τ2, I2, and subgroup analyses to examine heterogeneity. Of the 139 132 participants with no previous hospitalization with PAD, 32 489 (23.4%) reported job strain at baseline. During 1 718 132 person-years at risk (mean follow-up 12.8 years), 667 individuals had a hospital record of PAD (3.88 per 10 000 person-years). Job strain was associated with a 1.41-fold (95% CI, 1.11-1.80) increased average risk of hospitalization with PAD. The study-specific estimates were moderately heterogeneous (τ2=0.0427, I2: 26.9%). Despite variation in their magnitude, the estimates were consistent in both sexes, across the socioeconomic hierarchy and by baseline smoking status. Additional adjustment for baseline diabetes mellitus did not change the direction or magnitude of the observed associations. Conclusions Job strain was associated with small but consistent increase in the risk of hospitalization with PAD, with the relative risks on par with those for coronary heart disease and ischemic stroke.

Association between socioeconomic status and the development of mental and physical health conditions in adulthood: a multi-cohort study.

BACKGROUND: Socioeconomic disadvantage is a risk factor for many diseases. We characterised cascades of these conditions by using a data-driven approach to examine the association between socioeconomic status and temporal sequences in the development of 56 common diseases and health conditions. METHODS: In this multi-cohort study, we used data from two Finnish prospective cohort studies: the Health and Social Support study and the Finnish Public Sector study. Our pooled prospective primary analysis data comprised 109 246 Finnish adults aged 17-77 years at study entry. We captured socioeconomic status using area deprivation and education at baseline (1998-2013). Participants were followed up for health conditions diagnosed according to the WHO International Classification of Diseases until 2016 using linkage to national health records. We tested the generalisability of our findings with an independent UK cohort study-the Whitehall II study (9838 people, baseline in 1997, follow-up to 2017)-using a further socioeconomic status indicator, occupational position. FINDINGS: During 1 110 831 person-years at risk, we recorded 245 573 hospitalisations in the Finnish cohorts; the corresponding numbers in the UK study were 60 946 hospitalisations in 186 572 person-years. Across the three socioeconomic position indicators and after adjustment for lifestyle factors, compared with more advantaged groups, low socioeconomic status was associated with increased risk for 18 (32·1%) of the 56 conditions. 16 diseases formed a cascade of inter-related health conditions with a hazard ratio greater than 5. This sequence began with psychiatric disorders, substance abuse, and self-harm, which were associated with later liver and renal diseases, ischaemic heart disease, cerebral infarction, chronic obstructive bronchitis, lung cancer, and dementia. INTERPRETATION: Our findings highlight the importance of mental health and behavioural problems in setting in motion the development of a range of socioeconomically patterned physical illnesses. Policy and health-care practice addressing psychological health issues in social context and early in the life course could be effective strategies for reducing health inequalities. FUNDING: UK Medical Research Council, US National Institute on Aging, NordForsk, British Heart Foundation, Academy of Finland, and Helsinki Institute of Life Science.

Obesity and loss of disease-free years owing to major non-communicable diseases: a multicohort study.

BACKGROUND: Obesity increases the risk of several chronic diseases, but the extent to which the obesity-related loss of disease-free years varies by lifestyle category and across socioeconomic groups is unclear. We estimated the number of years free from major non-communicable diseases in adults who are overweight and obese, compared with those who are normal weight. METHODS: We pooled individual-level data on body-mass index (BMI) and non-communicable diseases from men and women with no initial evidence of these diseases in European cohort studies from the Individual-Participant-Data Meta-Analysis in Working Populations consortium. BMI was assessed at baseline (1991-2008) and non-communicable diseases (incident type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease) were ascertained via linkage to records from national health registries, repeated medical examinations, or self-report. Disease-free years from age 40 years to 75 years associated with underweight (BMI <18·5 kg/m2), overweight (≥25 kg/m2 to <30 kg/m2), and obesity (class I [mild] ≥30 kg/m2 to <35 kg/m2; class II-III [severe] ≥35 kg/m2) compared with normal weight (≥18·5 kg/m2 to <25 kg/m2) were estimated. FINDINGS: Of 137 503 participants from ten studies, we excluded 6973 owing to missing data and 10 349 with prevalent disease at baseline, resulting in an analytic sample of 120 181 participants. Of 47 127 men, 211 (0·4%) were underweight, 21 468 (45·6%) normal weight, 20 738 (44·0%) overweight, 3982 (8·4%) class I obese, and 728 (1·5%) class II-III obese. The corresponding numbers among the 73 054 women were 1493 (2·0%), 44 760 (61·3%), 19 553 (26·8%), 5670 (7·8%), and 1578 (2·2%), respectively. During 1 328 873 person-years at risk (mean follow-up 11·5 years [range 6·3-18·6]), 8159 men and 8100 women developed at least one non-communicable disease. Between 40 years and 75 years, the estimated number of disease-free years was 29·3 (95% CI 28·8-29·8) in normal-weight men and 29·4 (28·7-30·0) in normal-weight women. Compared with normal weight, the loss of disease-free years in men was 1·8 (95% CI -1·3 to 4·9) for underweight, 1·1 (0·7 to 1·5) for overweight, 3·9 (2·9 to 4·9) for class I obese, and 8·5 (7·1 to 9·8) for class II-III obese. The corresponding estimates for women were 0·0 (-1·4 to 1·4) for underweight, 1·1 (0·6 to 1·5) for overweight, 2·7 (1·5 to 3·9) for class I obese, and 7·3 (6·1 to 8·6) for class II-III obese. The loss of disease-free years associated with class II-III obesity varied between 7·1 and 10·0 years in subgroups of participants of different socioeconomic level, physical activity level, and smoking habit. INTERPRETATION: Mild obesity was associated with the loss of one in ten, and severe obesity the loss of one in four potential disease-free years during middle and later adulthood. This increasing loss of disease-free years as obesity becomes more severe occurred in both sexes, among smokers and non-smokers, the physically active and inactive, and across the socioeconomic hierarchy. FUNDING: NordForsk, UK Medical Research Council, US National Institute on Aging, Academy of Finland, Helsinki Institute of Life Science, and Cancer Research UK.

Work stress and risk of death in men and women with and without cardiometabolic disease: a multicohort study.

BACKGROUND: Although some cardiovascular disease prevention guidelines suggest a need to manage work stress in patients with established cardiometabolic disease, the evidence base for this recommendation is weak. We sought to clarify the status of stress as a risk factor in cardiometabolic disease by investigating the associations between work stress and mortality in men and women with and without pre-existing cardiometabolic disease. METHODS: In this multicohort study, we used data from seven cohort studies in the IPD-Work consortium, initiated between 1985 and 2002 in Finland, France, Sweden, and the UK, to examine the association between work stress and mortality. Work stress was denoted as job strain or effort-reward imbalance at work. We extracted individual-level data on prevalent cardiometabolic diseases (coronary heart disease, stroke, or diabetes [without differentiation by diabetes type]) at baseline. Work stressors, socioeconomic status, and conventional and lifestyle risk factors (systolic and diastolic blood pressure, total cholesterol, smoking status, BMI, physical activity, and alcohol consumption) were also assessed at baseline. Mortality data, including date and cause of death, were obtained from national death registries. We used Cox proportional hazards regression to study the associations of work stressors with mortality in men and women with and without cardiometabolic disease. RESULTS: We identified 102 633 individuals with 1 423 753 person-years at risk (mean follow-up 13·9 years [SD 3·9]), of whom 3441 had prevalent cardiometabolic disease at baseline and 3841 died during follow-up. In men with cardiometabolic disease, age-standardised mortality rates were substantially higher in people with job strain (149·8 per 10 000 person-years) than in those without (97·7 per 10 000 person-years; mortality difference 52·1 per 10 000 person-years; multivariable-adjusted hazard ratio [HR] 1·68, 95% CI 1·19-2·35). This mortality difference for job strain was almost as great as that for current smoking versus former smoking (78·1 per 10 000 person-years) and greater than those due to hypertension, high total cholesterol concentration, obesity, physical inactivity, and high alcohol consumption relative to the corresponding lower risk groups (mortality difference 5·9-44·0 per 10 000 person-years). Excess mortality associated with job strain was also noted in men with cardiometabolic disease who had achieved treatment targets, including groups with a healthy lifestyle (HR 2·01, 95% CI 1·18-3·43) and those with normal blood pressure and no dyslipidaemia (6·17, 1·74-21·9). In all women and in men without cardiometabolic disease, relative risk estimates for the work stress-mortality association were not significant, apart from effort-reward imbalance in men without cardiometabolic disease (mortality difference 6·6 per 10 000 person-years; multivariable-adjusted HR 1·22, 1·06-1·41). INTERPRETATION: In men with cardiometabolic disease, the contribution of job strain to risk of death was clinically significant and independent of conventional risk factors and their treatment, and measured lifestyle factors. Standard care targeting conventional risk factors is therefore unlikely to mitigate the mortality risk associated with job strain in this population. FUNDING: NordForsk, UK Medical Research Council, and Academy of Finland.

Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe.

BACKGROUND: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. METHODS: We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0-24·9 kg/m2), overweight (25·0-29·9 kg/m2), class I (mild) obesity (30·0-34·9 kg/m2), and class II and III (severe) obesity (≥35·0 kg/m2). We used an inclusive definition of underweight (<20 kg/m2) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis. FINDINGS: Participants were 120  813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease. INTERPRETATION: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes. FUNDING: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.

Job insecurity and risk of diabetes: a meta-analysis of individual participant data.

BACKGROUND: Job insecurity has been associated with certain health outcomes. We examined the role of job insecurity as a risk factor for incident diabetes. METHODS: We used individual participant data from 8 cohort studies identified in 2 open-access data archives and 11 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. We calculated study-specific estimates of the association between job insecurity reported at baseline and incident diabetes over the follow-up period. We pooled the estimates in a meta-analysis to produce a summary risk estimate. RESULTS: The 19 studies involved 140 825 participants from Australia, Europe and the United States, with a mean follow-up of 9.4 years and 3954 incident cases of diabetes. In the preliminary analysis adjusted for age and sex, high job insecurity was associated with an increased risk of incident diabetes compared with low job insecurity (adjusted odds ratio [OR] 1.19, 95% confidence interval [CI] 1.09-1.30). In the multivariable-adjusted analysis restricted to 15 studies with baseline data for all covariates (age, sex, socioeconomic status, obesity, physical activity, alcohol and smoking), the association was slightly attenuated (adjusted OR 1.12, 95% CI 1.01-1.24). Heterogeneity between the studies was low to moderate (age- and sex-adjusted model: I2 = 24%, p = 0.2; multivariable-adjusted model: I2 = 27%, p = 0.2). In the multivariable-adjusted analysis restricted to high-quality studies, in which the diabetes diagnosis was ascertained from electronic medical records or clinical examination, the association was similar to that in the main analysis (adjusted OR 1.19, 95% CI 1.04-1.35). INTERPRETATION: Our findings suggest that self-reported job insecurity is associated with a modest increased risk of incident diabetes. Health care personnel should be aware of this association among workers reporting job insecurity.

Long working hours and cancer risk: a multi-cohort study.

BACKGROUND: Working longer than the maximum recommended hours is associated with an increased risk of cardiovascular disease, but the relationship of excess working hours with incident cancer is unclear. METHODS: This multi-cohort study examined the association between working hours and cancer risk in 116 462 men and women who were free of cancer at baseline. Incident cancers were ascertained from national cancer, hospitalisation and death registers; weekly working hours were self-reported. RESULTS: During median follow-up of 10.8 years, 4371 participants developed cancer (n colorectal cancer: 393; n lung cancer: 247; n breast cancer: 833; and n prostate cancer: 534). We found no clear evidence for an association between working hours and the overall cancer risk. Working hours were also unrelated the risk of incident colorectal, lung or prostate cancers. Working ⩾55 h per week was associated with 1.60-fold (95% confidence interval 1.12-2.29) increase in female breast cancer risk independently of age, socioeconomic position, shift- and night-time work and lifestyle factors, but this observation may have been influenced by residual confounding from parity. CONCLUSIONS: Our findings suggest that working long hours is unrelated to the overall cancer risk or the risk of lung, colorectal or prostate cancers. The observed association with breast cancer would warrant further research.

Job strain and cardiovascular disease risk factors: meta-analysis of individual-participant data from 47,000 men and women.

BACKGROUND: Job strain is associated with an increased coronary heart disease risk, but few large-scale studies have examined the relationship of this psychosocial characteristic with the biological risk factors that potentially mediate the job strain - heart disease association. METHODOLOGY AND PRINCIPAL FINDINGS: We pooled cross-sectional, individual-level data from eight studies comprising 47,045 participants to investigate the association between job strain and the following cardiovascular disease risk factors: diabetes, blood pressure, pulse pressure, lipid fractions, smoking, alcohol consumption, physical inactivity, obesity, and overall cardiovascular disease risk as indexed by the Framingham Risk Score. In age-, sex-, and socioeconomic status-adjusted analyses, compared to those without job strain, people with job strain were more likely to have diabetes (odds ratio 1.29; 95% CI: 1.11-1.51), to smoke (1.14; 1.08-1.20), to be physically inactive (1.34; 1.26-1.41), and to be obese (1.12; 1.04-1.20). The association between job strain and elevated Framingham risk score (1.13; 1.03-1.25) was attributable to the higher prevalence of diabetes, smoking and physical inactivity among those reporting job strain. CONCLUSIONS: In this meta-analysis of work-related stress and cardiovascular disease risk factors, job strain was linked to adverse lifestyle and diabetes. No association was observed between job strain, clinic blood pressure or blood lipids.

Job strain and health-related lifestyle: findings from an individual-participant meta-analysis of 118,000 working adults.

OBJECTIVES: We examined the associations of job strain, an indicator of work-related stress, with overall unhealthy and healthy lifestyles. METHODS: We conducted a meta-analysis of individual-level data from 11 European studies (cross-sectional data: n = 118,701; longitudinal data: n = 43,971). We analyzed job strain as a set of binary (job strain vs no job strain) and categorical (high job strain, active job, passive job, and low job strain) variables. Factors used to define healthy and unhealthy lifestyles were body mass index, smoking, alcohol intake, and leisure-time physical activity. RESULTS: Individuals with job strain were more likely than those with no job strain to have 4 unhealthy lifestyle factors (odds ratio [OR] = 1.25; 95% confidence interval [CI] = 1.12, 1.39) and less likely to have 4 healthy lifestyle factors (OR = 0.89; 95% CI = 0.80, 0.99). The odds of adopting a healthy lifestyle during study follow-up were lower among individuals with high job strain than among those with low job strain (OR = 0.88; 95% CI = 0.81, 0.96). CONCLUSIONS: Work-related stress is associated with unhealthy lifestyles and the absence of stress is associated with healthy lifestyles, but longitudinal analyses suggest no straightforward cause-effect relationship between work-related stress and lifestyle.

Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data.

BACKGROUND: It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease. METHODS: We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985-2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2-4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death). RESULTS: There were 1086 incident events in 743,948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18-2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06-1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000). INTERPRETATION: The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain.

Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116,000 European men and women.

OBJECTIVE: To investigate whether work related stress, measured and defined as job strain, is associated with the overall risk of cancer and the risk of colorectal, lung, breast, or prostate cancers. DESIGN: Meta-analysis of pooled prospective individual participant data from 12 European cohort studies including 116,056 men and women aged 17-70 who were free from cancer at study baseline and were followed-up for a median of 12 years. Work stress was measured and defined as job strain, which was self reported at baseline. Incident cancers (all n=5765, colorectal cancer n=522, lung cancer n=374, breast cancer n=1010, prostate cancer n=865) were ascertained from cancer, hospital admission, and death registers. Data were analysed in each study with Cox regression and the study specific estimates pooled in meta-analyses. Models were adjusted for age, sex, socioeconomic position, body mass index (BMI), smoking, and alcohol intake RESULTS: A harmonised measure of work stress, high job strain, was not associated with overall risk of cancer (hazard ratio 0.97, 95% confidence interval 0.90 to 1.04) in the multivariable adjusted analyses. Similarly, no association was observed between job strain and the risk of colorectal (1.16, 0.90 to 1.48), lung (1.17, 0.88 to 1.54), breast (0.97, 0.82 to 1.14), or prostate (0.86, 0.68 to 1.09) cancers. There was no clear evidence for an association between the categories of job strain and the risk of cancer. CONCLUSIONS: These findings suggest that work related stress, measured and defined as job strain, at baseline is unlikely to be an important risk factor for colorectal, lung, breast, or prostate cancers.

Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data.

BACKGROUND: Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies. METHODS: We used individual records from 13 European cohort studies (1985-2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. FINDINGS: 30,214 (15%) of 197,473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10-1·37). This effect estimate was higher in published (1·43, 1·15-1·77) than unpublished (1·16, 1·02-1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15-1·48) and 5 years (1·30, 1·13-1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%. INTERPRETATION: Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking. FUNDING: Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.

Job strain and tobacco smoking: an individual-participant data meta-analysis of 166,130 adults in 15 European studies.

BACKGROUND: Tobacco smoking is a major contributor to the public health burden and healthcare costs worldwide, but the determinants of smoking behaviours are poorly understood. We conducted a large individual-participant meta-analysis to examine the extent to which work-related stress, operationalised as job strain, is associated with tobacco smoking in working adults. METHODOLOGY AND PRINCIPAL FINDINGS: We analysed cross-sectional data from 15 European studies comprising 166,130 participants. Longitudinal data from six studies were used. Job strain and smoking were self-reported. Smoking was harmonised into three categories never, ex- and current. We modelled the cross-sectional associations using logistic regression and the results pooled in random effects meta-analyses. Mixed effects logistic regression was used to examine longitudinal associations. Of the 166,130 participants, 17% reported job strain, 42% were never smokers, 33% ex-smokers and 25% current smokers. In the analyses of the cross-sectional data, current smokers had higher odds of job strain than never-smokers (age, sex and socioeconomic position-adjusted odds ratio: 1.11, 95% confidence interval: 1.03, 1.18). Current smokers with job strain smoked, on average, three cigarettes per week more than current smokers without job strain. In the analyses of longitudinal data (1 to 9 years of follow-up), there was no clear evidence for longitudinal associations between job strain and taking up or quitting smoking. CONCLUSIONS: Our findings show that smokers are slightly more likely than non-smokers to report work-related stress. In addition, smokers who reported work stress smoked, on average, slightly more cigarettes than stress-free smokers.