Preterm birth and the risk of multimorbidity in adolescence: a multiregister-based cohort study.

BACKGROUND: Multimorbidity affects people of all ages, but the risk factors of multimorbidity in adolescence are unclear. The aim of this study was to examine preterm birth (<37 weeks) as a shared risk factor for multiple health outcomes and the role of gestational age (degree of prematurity) in the development of increasingly complex multimorbidity (two, three, or four health outcomes) in adolescence (age 10-18 years). METHODS: We used population-wide data from Finland (1 187 610 adolescents born 1987-2006) and Norway (555 431 adolescents born 1998-2007). Gestational age at birth was ascertained from medical birth registers and categorised as 23-27 weeks (extremely preterm), 28-31 weeks (very preterm), 32-33 weeks (moderately preterm), 34-36 weeks (late preterm), 37-38 weeks (early term), 39-41 weeks (term, reference category) and 42-44 weeks (post-term). Children who died or emigrated before their 10th birthday, and those with missing or implausible data on gestational age, birthweight, or covariates, were excluded. Health outcomes at age 10-18 years were ascertained from specialised health care and mortality registers. We calculated hazard ratios (HRs) and population attributable fractions (PAFs) with 95% CIs for multiple health outcomes during adolescence. FINDINGS: Individuals were followed up from age 10 to 18 years (mean follow-up: 6 years, SD: 3 years). Preterm birth was associated with increased risks of 20 hospital-treated malignant, cardiovascular, endocrinological, neuropsychiatric, respiratory, genitourinary, and congenital health outcomes, after correcting for multiple testing and ignoring small effects (HR <1·2). Confounder-adjusted HRs comparing preterm with term-born adolescents were 2·29 (95% CI 2·19-2·39) for two health outcomes (PAF 9·0%; 8·3-9·6), and 4·22 (3·66-4·87) for four health outcomes (PAF 22·7%; 19·4-25·8) in the Finnish data. Results in the Norwegian data showed a similar pattern. We observed a consistent dose-response relationship between an earlier gestational age and elevated risks of increasingly complex multimorbidity in both datasets. INTERPRETATION: Preterm birth is associated with increased risks of diverse multimorbidity patterns at age 10-18 years. Adolescents with a preterm-born background could benefit from diagnostic vigilance directed at multimorbidity and a multidisciplinary approach to health care. FUNDING: European Union Horizon 2020, Academy of Finland, Foundation for Pediatric Research, Sigrid Jusélius Foundation, Signe and Ane Gyllenberg Foundation.

Preterm birth and asthma and COPD in adulthood: a nationwide register study from two Nordic countries.

BACKGROUND: Preterm birth affects lungs in several ways but few studies have follow-up until adulthood. We investigated the association of the entire spectrum of gestational ages with specialist care episodes for obstructive airway disease (asthma and chronic obstructive pulmonary disease (COPD)) at age 18-50 years. METHODS: We used nationwide registry data on 706 717 people born 1987-1998 in Finland (4.8% preterm) and 1 669 528 born 1967-1999 in Norway (5.0% preterm). Care episodes of asthma and COPD were obtained from specialised healthcare registers, available in Finland for 2005-2016 and in Norway for 2008-2017. We used logistic regression to estimate odds ratios (ORs) for having a care episode with either disease outcome. RESULTS: Odds of any obstructive airway disease in adulthood for those born at <28 or 28-31 completed weeks were 2-3-fold of those born full term (39-41 completed weeks), persisting after adjustments. For individuals born at 32-33, 34-36 or 37-38 weeks, the odds were 1.1- to 1.5-fold. Associations were similar in the Finnish and the Norwegian data and among people aged 18-29 and 30-50 years. For COPD at age 30-50 years, the OR was 7.44 (95% CI 3.49-15.85) for those born at <28 weeks, 3.18 (95% CI 2.23-4.54) for those born at 28-31 weeks and 2.32 (95% CI 1.72-3.12) for those born at 32-33 weeks. Bronchopulmonary dysplasia in infancy increased the odds further for those born at <28 and 28-31 weeks. CONCLUSION: Preterm birth is a risk factor for asthma and COPD in adulthood. The high odds of COPD call for diagnostic vigilance when adults born very preterm present with respiratory symptoms.

Association of neighbourhood deprivation with risks of major amputation and death following lower limb revascularisation.

BACKGROUND AND AIMS: Individual-level socioeconomic deprivation is associated with an increased risk of adverse patient outcomes following cardiovascular disease interventions, but the role of area-level socioeconomic circumstances as a predictor for treatment outcomes is unclear. We have examined the association of neighbourhood socioeconomic deprivation with risks of major lower limb amputation and death following surgical and endovascular lower limb revascularisation due to peripheral artery disease (PAD). METHODS: Patients aged 50+ years who underwent surgical or endovascular lower limb revascularisation for PAD were identified from Hospital Episode Statistics, a nationwide hospital data warehouse in England. Major amputations and deaths within a year of revascularisation were ascertained from HES and national mortality register, respectively. Index of Multiple Deprivation (IMD) was used to measure neighbourhood deprivation. Flexible parametric competing risks models were used to estimate sub-distribution hazard ratios (SHRs) for amputation and death. RESULTS: In all, 65,806 patients underwent endovascular and 20,072 underwent surgical revascularisation. The covariate-adjusted 1-year risk of major amputation was higher among patients from the most deprived compared to least deprived neighbourhoods following endovascular revascularisation (SHR: 1.24, 95% confidence interval, CI:1.10 to 1.38) and surgical revascularisation (SHR:1.28, 95% CI: 1.09 to 1.51). The risk of death was higher in most deprived compared to the least deprived neighbourhoods following both procedures. CONCLUSIONS: We found a consistent association between neighbourhood deprivation and amputation and death outcomes following lower limb revascularisation for PAD. These findings suggest there may be opportunities for targeted interventions to improve care of PAD patients in deprived neighbourhoods.

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 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.

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.

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.

Celiac disease autoimmunity and hip fracture risk: findings from a prospective cohort study.

The impact of celiac disease autoimmunity on bone health is unclear. We investigated the associations of seropositivity for tissue transglutaminase antibodies (tTGA) and endomysial antibodies (EMA) with incident hip fractures using data from a prospective cohort study, Mini-Finland Health Survey. Baseline serum samples, taken in 1978-80, were tested for tTGA and EMA. Incident hip fractures up to the year 2011 were ascertained from a national hospitalization register. Associations between seropositivity and hip fractures were modeled using Cox proportional hazards regression adjusted for age, sex, body mass index, vitamin D, gamma-glutamyl transferase, smoking, and self-rated health. Our analyses were based on 6919 men and women who had no record of celiac disease or hip fracture before the study baseline. A total of 382 individuals had a hip fracture during a median follow-up of 30 years. Compared with the tTGA-negative individuals (n = 6350), tTGA-positive participants (n = 569; with hip fracture, n = 51) had a higher risk of hip fractures (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.17, 2.14). The findings were similar for another tTGA test (n 200; with hip fracture, n = 26; HR = 2.23, 95% CI 1.49, 3.34). We found no evidence for an association between EMA positivity and hip fracture risk (HR = 0.92, 95% CI 0.34, 2.47; n = 74; with hip fracture, n = 4). In our prospective population-based study of Finnish adults, seropositivity for tTGA was associated with an increased hip fracture risk.

Breastfeeding and educational achievement at age 5.

Our aim was to investigate whether the duration of breastfeeding, at all or exclusively, is associated with educational achievement at age 5. We used data from a prospective, population-based UK cohort study, the Millennium Cohort Study (MCS). 5489 children from White ethnic background born at term in 2000-2001, attending school in England in 2006, were included in our analyses. Educational achievement was measured using the Foundation Stage Profile (FSP), a statutory assessment undertaken by teachers at the end of the child's first school year. Breastfeeding duration was ascertained from interviews with the mother when the child was 9 months old. We used modified Poisson's regression to model the association of breastfeeding duration with having reached a good level of achievement overall (≥78 overall points and ≥6 in 'personal, social and emotional development' and 'communication, language and literacy' points) and in specific areas (≥6 points) of development. Children who had been breastfed for up to 2 months were more likely to have reached a good level of overall achievement [adjusted rate ratio (RR): 1.09, 95% confidence interval (CI): 1.01, 1.19] than never breastfed children. This association was more marked in children breastfed for 2-4 months (adjusted RR: 1.17, 95% CI: 1.07, 1.29) and in those breastfed for longer than 4 months (adjusted RR: 1.16, 95% CI: 1.07, 1.26). The associations of exclusive breastfeeding with the educational achievement were similar. Our findings suggest that longer duration of breastfeeding, at all or exclusively, is associated with better educational achievement at age 5.

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.

C-reactive protein-associated genetic variants and cancer risk: findings from FINRISK 1992, FINRISK 1997 and Health 2000 studies.

BACKGROUND: Evidence from prospective observational studies suggests that elevated circulating C-reactive protein (CRP) concentrations are associated with cancer risk, but it is unclear whether this association is causal. In order to examine this, we investigated whether genetic variants that are associated with circulating CRP concentrations are associated with cancer risk. METHODS: We pooled data from three population-based prospective Finnish studies: FINRISK 1992 (n = 5289), FINRISK 1997 (n = 7160) and Health 2000 (n = 6299). Cancer cases were identified from cancer registrations. Thirteen CRP-associated SNPs, identified from genome-wide association studies, were genotyped. We examined the associations of the SNPs and cancer risk using Cox, probit and instrumented probit regression models. RESULTS: Compared to common allele homozygotes, individuals carrying one or two variant T alleles at rs1892534 had 1.05-fold (95% confidence interval (CI): 0.90, 1.23) and 1.2-fold (95% CI: 1.01, 1.42) increased overall cancer risk, respectively. Individuals with one or two variant A alleles at rs1169300 or rs2464196 had approximately 1.5- and 2-fold increased risk of lung cancer, respectively (p trend for both: 0.007). CRP SNPs were not associated with colorectal, prostate or breast cancer risk nor was CRP-associated with the probability of developing cancer in the instrumented probit analyses. CONCLUSIONS: We found some evidence for an association of a small number of CRP-associated SNPs with the overall cancer risk and lung cancer risk. Our instrumental variable analyses provided no clear evidence for a causal association of CRP and cancer. These findings suggest that circulating CRP concentrations are unlikely to have a causal role in cancer.

Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis.

OBJECTIVE: We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk. METHODS: We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women's Heart and Health Study (4,286 women aged 60-80) and the Caerphilly Cohort (2,398 men aged 45-59) using Cox regression and pooled our findings with previous prospective studies' in fixed and random effects meta-analyses. RESULTS: CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk. CONCLUSIONS: Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

Systematic review of the association between circulating interleukin-6 (IL-6) and cancer.

Our aim was to systematically review the epidemiologic evidence for an association of circulating interleukin-6 (IL-6), an inflammatory cytokine and cancer. We systematically searched electronic databases Embase, Medline and Web of Science for the studies of circulating IL-6 and any form of cancer. We identified and reviewed 189 discrete studies, consisting of 177 prevalent studies and three prospective studies. Cancer patients' IL-6 concentrations were higher than healthy controls' in most studies, but the results of investigations comparing IL-6 in cancer patients and individuals with benign diseases were less consistent. Due to the small number of prospective studies it is impossible to determine whether IL-6 is causally related to cancer. Large prospective studies of circulating IL-6 or studies using the functional variants of the IL-6 gene as instruments for circulating IL-6 concentrations would provide information on possible aetiological links between IL-6 and malignancy.