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1.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
The funding sources are cited at the end of the paper.
PMCID: PMC4322187  PMID: 25262344
2.  Glycemia, Insulin Resistance, Insulin Secretion, and Risk of Depressive Symptoms in Middle Age 
Diabetes Care  2013;36(4):928-934.
The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS).
In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up.
Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25–3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex.
Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.
PMCID: PMC3609527  PMID: 23230097
3.  Education Modifies the Association of Wealth with Obesity in Women in Middle-Income but Not Low-Income Countries: An Interaction Study Using Seven National Datasets, 2005-2010 
PLoS ONE  2014;9(3):e90403.
Education and wealth may have different associations with female obesity but this has not been investigated in detail outside high-income countries. This study examines the separate and inter-related associations of education and household wealth in relation to obesity in women in a representative sample of low- and middle-income countries (LMICs).
The seven largest national surveys were selected from a list of Demographic and Health Surveys (DHS) ordered by decreasing sample size and resulted in a range of country income levels. These were nationally representative data of women aged 15–49 years collected in the period 2005–2010. The separate and joint effects, unadjusted and adjusted for age group, parity, and urban/rural residence using a multivariate logistic regression model are presented
In the four middle-income countries (Colombia, Peru, Jordan, and Egypt), an interaction was found between education and wealth on obesity (P-value for interaction <0.001). Among women with no/primary education the wealth effect was positive whereas in the group with higher education it was either absent or inverted (negative). In the poorer countries (India, Nigeria, Benin), there was no evidence of an interaction. Instead, the associations between each of education and wealth with obesity were independent and positive. There was a statistically significant difference between the average interaction estimates for the low-income and middle-income countries (P<0.001).
The findings suggest that education may protect against the obesogenic effects of increased household wealth as countries develop. Further research could examine the factors explaining the country differences in education effects.
PMCID: PMC3946446  PMID: 24608086
4.  Life Course Socioeconomic Position and Mid-Late Life Cognitive Function in Eastern Europe 
To investigate whether the positive relation between socioeconomic position (SEP) across the life course and later life cognitive function observed in Western populations exists in former communist countries with apparently smaller income inequalities.
Structural equation modeling analysis of cross-sectional data on 30,846 participants aged 45–78 years in four Central and Eastern European centers: Novosibirsk (Russia), Krakow (Poland), Kaunas (Lithuania), and six Czech towns from the HAPIEE (Health, Alcohol, and Psychosocial factors In Eastern Europe) study. SEP was measured using self-reported childhood (maternal education, household amenities), adult (education), and older adult (current material circumstances) indicators. Latent variable for cognition was constructed from word recall, animal naming, and letter search.
Associations between SEP measures over the life course and cognition were similar across study centers. Education had the strongest direct association with cognition, followed by current material circumstances. Indirect path from education to cognition, mediated by current SEP, was small. Direct path from mother’s education to cognition was significant but modest, and partially mediated by later SEP measures, particularly education.
In these Eastern European populations, late life cognition reflected life course socioeconomic trajectories similarly to findings in Western countries.
PMCID: PMC3983917  PMID: 24598045
Cognitive aging; Eastern Europe; Life course; Socioeconomic position.
5.  Association between common mental disorder and obesity over the adult lifecourse 
Prospective data on the association between common mental disorders and obesity are scarce, and the impact of ageing on this association is poorly understood.
To examine the association between common mental disorders and obesity (BMI≥30 kg/m2) across the adult life course.
6832 men and 3348 women aged 35-55 were screened 4 times during a 19-year follow-up (the Whitehall II study). Each screening included measurements of mental disorders (the General Health Questionnaire), weight, and height.
The excess risk of obesity in the presence of mental disorders increased with age (p=0.004). The estimated proportion of obese people was 5.7% at age 40 both in the presence and absence of mental disorders, but the corresponding figures were 34.6% and 27.1% at age 70. The excess risk did not vary by sex or according to ethnic group or socioeconomic position.
The association between common mental disorders and obesity becomes stronger at older ages.
Conflict of interest
No conflict of interest declared (MK, GDB, ASM, HN, SS, AGT, TNA, JV, MGM, MJ)
PMCID: PMC2770241  PMID: 19648547
7.  Unfairness and health: evidence from the Whitehall II Study 
To examine the effects of unfairness on incident coronary events and health functioning.
Prospective cohort study. Unfairness, sociodemographics, established coronary risk factors (high serum cholesterol, hypertension, obesity, exercise, smoking and alcohol consumption) and other psychosocial work characteristics (job strain, effort–reward imbalance and organisational justice) were measured at baseline. Associations between unfairness and incident coronary events and health functioning were determined over an average follow‐up of 10.9 years.
5726 men and 2572 women from 20 civil service departments in London (the Whitehall II Study).
Main outcome measures
Incident fatal coronary heart disease, non‐fatal myocardial infarction and angina (528 events) and health functioning.
Low employment grade is strongly associated with unfairness. Participants reporting higher levels of unfairness are more likely to experience an incident coronary event (HR 1.55, 95% CI 1.11 to 2.17), after adjustment for age, gender, employment grade, established coronary risk factors and other work‐related psychosocial characteristics. Unfairness is also associated with poor physical (OR 1.46, 95% CI 1.20 to 1.77) and mental (OR 1.54, 95% CI 1.19 to 1.99) functioning at follow‐up, controlling for all other factors and health functioning at baseline.
Unfairness is an independent predictor of increased coronary events and impaired health functioning. Further research is needed to disentangle the effects of unfairness from other psychosocial constructs and to investigate the societal, relational and biological mechanisms that may underlie its associations with health and heart disease.
PMCID: PMC2465722  PMID: 17496260
8.  Education is associated with lower levels of abdominal obesity in women with a non-agricultural occupation: an interaction study using China’s four provinces survey 
BMC Public Health  2013;13:769.
The prevalence of obesity is increasing rapidly in low- and middle-income countries (LMICs) as their populations become exposed to obesogenic environments. The transition from an agrarian to an industrial and service-based economy results in important lifestyle changes. Yet different socioeconomic groups may experience and respond to these changes differently. Investigating the socioeconomic distribution of obesity in LMICs is key to understanding the causes of obesity but the field is limited by the scarcity of data and a uni-dimensional approach to socioeconomic status (SES). This study splits socioeconomic status into two dimensions to investigate how educated women may have lower levels of obesity in a context where labour market opportunities have shifted away from agriculture to other forms of employment.
The Four Provinces Study in China 2008/09 is a household-based community survey of 4,314 people aged ≥60  years (2,465 women). It was used to investigate an interaction between education (none/any) and occupation (agricultural/non-agricultural) on high-risk central obesity defined as a waist circumference ≥80 cm. An interaction term between education and occupation was incorporated in a multivariate logistic regression model, and the estimates adjusted for age, parity, urban/rural residence and health behaviours (smoking, alcohol, meat and fruit & vegetable consumption). Complete case analyses were undertaken and results confirmed using multiple imputation to impute missing data.
An interaction between occupation and education was present (P = 0.02). In the group with no education, the odds of central obesity in the sedentary occupation group were more than double those of the agricultural occupation group even after taking age group and parity into account (OR; 95%CI: 2.21; 1.52, 3.21), while in the group with any education there was no evidence of such a relationship (OR; 95%CI: 1.25; 0.92, 1.70). Health behaviours appeared to account for some of the association.
These findings suggest that education may have a protective role in women against the higher odds of obesity associated with occupational shifts in middle-income countries, and that investment in women’s education may present an important long term investment in obesity prevention. Further research could elucidate the mechanisms behind this association.
PMCID: PMC3844357  PMID: 23962144
Socioeconomic status; Obesity; Low- and middle-income countries; Epidemiology; Women; China; Education; Occupation; Waist circumference; Transition
9.  Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study 
PLoS Medicine  2013;10(7):e1001479.
Silvia Stringhini and colleagues followed a group of British civil servants over 18 years to look for links between socioeconomic status and health.
Please see later in the article for the Editors' Summary
Socioeconomic adversity in early life has been hypothesized to “program” a vulnerable phenotype with exaggerated inflammatory responses, so increasing the risk of developing type 2 diabetes in adulthood. The aim of this study is to test this hypothesis by assessing the extent to which the association between lifecourse socioeconomic status and type 2 diabetes incidence is explained by chronic inflammation.
Methods and Findings
We use data from the British Whitehall II study, a prospective occupational cohort of adults established in 1985. The inflammatory markers C-reactive protein and interleukin-6 were measured repeatedly and type 2 diabetes incidence (new cases) was monitored over an 18-year follow-up (from 1991–1993 until 2007–2009). Our analytical sample consisted of 6,387 non-diabetic participants (1,818 women), of whom 731 (207 women) developed type 2 diabetes over the follow-up. Cumulative exposure to low socioeconomic status from childhood to middle age was associated with an increased risk of developing type 2 diabetes in adulthood (hazard ratio [HR] = 1.96, 95% confidence interval: 1.48–2.58 for low cumulative lifecourse socioeconomic score and HR = 1.55, 95% confidence interval: 1.26–1.91 for low-low socioeconomic trajectory). 25% of the excess risk associated with cumulative socioeconomic adversity across the lifecourse and 32% of the excess risk associated with low-low socioeconomic trajectory was attributable to chronically elevated inflammation (95% confidence intervals 16%–58%).
In the present study, chronic inflammation explained a substantial part of the association between lifecourse socioeconomic disadvantage and type 2 diabetes. Further studies should be performed to confirm these findings in population-based samples, as the Whitehall II cohort is not representative of the general population, and to examine the extent to which social inequalities attributable to chronic inflammation are reversible.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, more than 350 million people have diabetes, a metabolic disorder characterized by high amounts of glucose (sugar) in the blood. Blood sugar levels are normally controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest form of diabetes) blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes, which was previously called adult-onset diabetes, can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. However, as the disease progresses, the pancreatic beta cells, which make insulin, become impaired and patients may eventually need insulin injections. Long-term complications, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Socioeconomic adversity in childhood seems to increase the risk of developing type 2 diabetes but why? One possibility is that chronic inflammation mediates the association between socioeconomic adversity and type 2 diabetes. Inflammation, which is the body's normal response to injury and disease, affects insulin signaling and increases beta-cell death, and markers of inflammation such as raised blood levels of C-reactive protein and interleukin 6 are associated with future diabetes risk. Notably, socioeconomic adversity in early life leads to exaggerated inflammatory responses later in life and people exposed to social adversity in adulthood show greater levels of inflammation than people with a higher socioeconomic status. In this prospective cohort study (an investigation that records the baseline characteristics of a group of people and then follows them to see who develops specific conditions), the researchers test the hypothesis that chronically increased inflammatory activity in individuals exposed to socioeconomic adversity over their lifetime may partly mediate the association between socioeconomic status over the lifecourse and future type 2 diabetes risk.
What Did the Researchers Do and Find?
To assess the extent to which chronic inflammation explains the association between lifecourse socioeconomic status and type 2 diabetes incidence (new cases), the researchers used data from the Whitehall II study, a prospective occupational cohort study initiated in 1985 to investigate the mechanisms underlying previously observed socioeconomic inequalities in disease. Whitehall II enrolled more than 10,000 London-based government employees ranging from clerical/support staff to administrative officials and monitored inflammatory marker levels and type 2 diabetes incidence in the study participants from 1991–1993 until 2007–2009. Of 6,387 participants who were not diabetic in 1991–1993, 731 developed diabetes during the 18-year follow-up. Compared to participants with the highest cumulative lifecourse socioeconomic score (calculated using information on father's occupational position and the participant's educational attainment and occupational position), participants with the lowest score had almost double the risk of developing diabetes during follow-up. Low lifetime socioeconomic status trajectories (being socially downwardly mobile or starting and ending with a low socioeconomic status) were also associated with an increased risk of developing diabetes in adulthood. A quarter of the excess risk associated with cumulative socioeconomic adversity and nearly a third of the excess risk associated with low socioeconomic trajectory was attributable to chronically increased inflammation.
What Do These Findings Mean?
These findings show a robust association between adverse socioeconomic circumstances over the lifecourse of the Whitehall II study participants and the risk of type 2 diabetes and suggest that chronic inflammation explains up to a third of this association. The accuracy of these findings may be affected by the measures of socioeconomic status used in the study. Moreover, because the study participants were from an occupational cohort, these findings need to be confirmed in a general population. Studies are also needed to examine the extent to which social inequalities in diabetes risk that are attributable to chronic inflammation are reversible. Importantly, if future studies confirm and extend the findings reported here, it might be possible to reduce the social inequalities in type 2 diabetes by promoting interventions designed to reduce inflammation, including weight management, physical activity, and smoking cessation programs and the use of anti-inflammatory drugs, among socially disadvantaged groups.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals, and the general public, including information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes; it includes peoples stories about diabetes
The nonprofit Diabetes UK also provides detailed information about diabetes for patients and carers, including information on healthy lifestyles for people with diabetes, and has a further selection of stories from people with diabetes; the nonprofit Healthtalkonline has interviews with people about their experiences of diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
Information about the Whitehall II study is available
PMCID: PMC3699448  PMID: 23843750
10.  Job Strain and Cardiovascular Disease Risk Factors: Meta-Analysis of Individual-Participant Data from 47,000 Men and Women 
PLoS ONE  2013;8(6):e67323.
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.
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.
PMCID: PMC3688665  PMID: 23840664
11.  The impact of cash transfers to poor women in Colombia on BMI and obesity: prospective cohort study 
Prevalence of obesity is rising in Latin America, is increasingly affecting socially disadvantaged groups, particularly women. Conditional cash transfers are recently established welfare interventions in the region. One, Familias en Accion, transfers ~20% of average monthly income to women in Colombia’s poorest families. Previous work has found that families buy more food as a result.
We tested the hypothesis that participation in Familias would be associated with increasing body mass index (BMI) in participating women
Women from participating areas and control areas (matched on environmental and socioeconomic criteria) were surveyed in 2002 and 2006. Pregnant, breast-feeding or women aged<18 or with BMI<18.5kg/m2 were excluded. The sample comprises 835 women from control and 1238 from treatment areas. Because some treatment areas started Familias shortly before baseline data collection, a dummy variable was created that identified exposure independent of time-point or area. Follow-up was 61.5%.
BMI was measured by trained personnel using standardized techniques. Overweight was defined as BMI>25kg/m2 and obesity as >30kg/m2. The effect of Familias was estimated using linear regression (or logistic regression for dichotomous outcomes) in a double-difference technique, controlling for several individual, household and area characteristics, including parity and baseline BMI, using robust standard-errors clustered at area-level in an intention-to-treat analysis.
At baseline, women’s mean age was 33.3 years and mean BMI 25.3kg/m2; 12.3% women were obese. After adjustment, exposure to Familias was significantly associated with increased BMI (β=0.25, 95% CI 0.03, 0.47; p=0.03). Age (β=0.09; 95%CI 0.06, 0.13; p<0.001) and household wealth (β=0.78; 95%CI 0.41, 1.15; p<0.001) were also positively associated with BMI. Familias was also associated with increased odds of obesity (O.R.=1.27 95%CI 1.03, 1.57; p=0.03), as was age (O.R.=1.04; 95%CI 1.02, 1.06; p=0.001).
Conditional cash transfers to poor women in Colombia are independently associated with increasing BMI and obesity risk. Although conditional cash transfers are generally regarded as popular and successful schemes, parallel interventions at individual, household and community level are needed to avoid unanticipated adverse outcomes.
PMCID: PMC3378481  PMID: 22143619
14.  Job Strain as a Risk Factor for Leisure-Time Physical Inactivity: An Individual-Participant Meta-Analysis of Up to 170,000 Men and Women 
American Journal of Epidemiology  2012;176(12):1078-1089.
Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 1985–1988 to 2006–2008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50% women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 2–9 years. In cross-sectional analyses, the odds for physical inactivity were 26% higher (odds ratio = 1.26, 95% confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21% higher (odds ratio = 1.21, 95% confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21% and 20% higher for those with high-strain (odds ratio = 1.21, 95% confidence interval: 1.11, 1.32) and passive (odds ratio = 1.20, 95% confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.
PMCID: PMC3521479  PMID: 23144364
cohort studies; exercise; physical activity; psychosocial factors; working population
15.  Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data 
Lancet  2012;380(9852):1491-1497.
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.
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.
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%.
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.
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.
PMCID: PMC3486012  PMID: 22981903
16.  Combined Effects of Depressive Symptoms and Resting Heart Rate on Mortality: The Whitehall II Prospective Cohort Study 
The Journal of clinical psychiatry  2010;72(9):1199-1206.
To examine the combined effects of depressive symptoms and resting heart rate (RHR) on mortality.
Data come from 5936 participants, aged 61 ± 6 years, from the Whitehall II study. Depressive symptoms were assessed in 2002–2004 using the center-for-epidemiologic-studies-depression-scale (score ≥ 16). RHR was measured at the same study phase via electrocardiogram. Participants were assigned to 1 of 6 risk-factor-groups based on depression status (yes/no) and RHR categories (<60, 60 – 80, >80 bpm). Mean follow-up for mortality was 5.6 years.
In mutually adjusted Cox regression models, depression (hazard ratio = 1.93 p<0.001) and RHR>80 bpm (hazard ratio = 1.67, p<0.001) were independent predictors of mortality. After adjustment for potential confounding and mediating variables, participants with both depression and high RHR had a 3.0-fold higher (p<0.001) risk of death compared to depression-free participants with RHR ranging from 60 to 80 bpm. This risk is particularly marked in participants with prevalent CHD.
This study provides evidence that the coexistence of depressive symptoms and elevated RHR is associated with substantially increased risk of death compared to those without these two factors. This finding raises the possibility that treatments that improve both depression and RHR might improve survival.
PMCID: PMC3226937  PMID: 21208592
depression; resting heart rate and mortality
17.  Economic difficulties and physical functioning in Finnish and British employees: contribution of social and behavioural factors 
Background: Childhood and current economic difficulties are associated with physical health. However, evidence concerning the factors underlying these associations is sparse. This study examines the contribution of a range of social and behavioural factors to associations between economic difficulties and physical functioning. Methods: We used comparable data on middle-aged white-collar employees from the Finnish Helsinki Health Study cohort (n = 3843) and the British Whitehall II Study cohort (n = 3052). Our health outcome was physical functioning measured by the SF-36 Physical Component Summary. Relative indices of inequality (RII), calculated using logistic regression analysis, were used to examine associations between economic difficulties and physical functioning, and the contribution of further socio-economic circumstances, health behaviours, living arrangements and work–family conflicts to these associations. Results: In age-adjusted models, childhood (RII = 1.76−3.06) and current (RII = 1.79−3.03) economic difficulties were associated with poor physical functioning in both cohorts. Further adjusting for work–family conflicts attenuated the associations of current economic difficulties with physical functioning in both cohorts, and also those of childhood economic difficulties in the Helsinki cohort. Adjustments for other socio-economic circumstances also caused some attenuation, while health behaviours and living arrangements had small or negligible effects. Conclusions: Conflicts between work and family contribute to the associations of economic difficulties with physical functioning among employees from Finland and Britain. This suggests that supporting people to cope with economic difficulties, and efforts to improve the balance between paid work and family may help employees maintain good physical functioning.
PMCID: PMC3139100  PMID: 20616102
comparisons; employees; physical functioning; SF-36; socio-economic position
18.  Does cognitive reserve shape cognitive decline? 
Annals of neurology  2011;70(2):296-304.
Cognitive reserve is associated with a lower risk of dementia but the extent to which it shapes cognitive aging trajectories remains unclear. Our objective is to examine the impact of three markers of reserve from different points in the lifecourse on cognitive function and decline in late adulthood.
Data are from 5234 men and 2220 women, mean age 56 years (standard deviation=6) at baseline, from the Whitehall II cohort study. Memory, reasoning, vocabulary, phonemic and semantic fluency were assessed three times over 10 years. Linear mixed models were used to assess the association between markers of reserve (height, education, and occupation) and cognitive decline, using the 5 cognitive tests and a global cognitive score composed of these tests.
All three reserve measures were associated with baseline cognitive function, with strongest associations with occupation and the weakest with height. All cognitive functions except vocabulary declined over the 10 year follow-up period. On the global cognitive test, there was greater decline in the high occupation group (−0.27; 95% confidence interval (CI): −0.28, −0.26) compared to the intermediate (−0.23; 95% CI: −0.25, −0.22) and low groups (−0.21; 95% CI: −0.24, −0.19); p=0.001. The decline in reserve groups defined by education (p=0.82) and height (p=0.55) was similar.
Cognitive performance over the adult lifecourse was remarkably higher in the high reserve groups. However, rate of cognitive decline did not differ between reserve groups except occupation where there was some evidence of greater decline in the high occupation group.
PMCID: PMC3152621  PMID: 21563209
19.  Job Strain and Tobacco Smoking: An Individual-Participant Data Meta-Analysis of 166 130 Adults in 15 European Studies 
PLoS ONE  2012;7(7):e35463.
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.
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.
PMCID: PMC3391192  PMID: 22792154
20.  Job Strain and Alcohol Intake: A Collaborative Meta-Analysis of Individual-Participant Data from 140 000 Men and Women 
PLoS ONE  2012;7(7):e40101.
The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake.
Methodology and Principal Findings
We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1–14, men: 1–21 drinks/week), intermediate (women: 15–20, men: 22–27 drinks/week) and heavy (women: >20, men: >27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake.
Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.
PMCID: PMC3391232  PMID: 22792218
21.  Interaction between Education and Household Wealth on the Risk of Obesity in Women in Egypt 
PLoS ONE  2012;7(6):e39507.
Obesity is a growing problem in lower income countries particularly among women. There are few studies exploring individual socioeconomic status indicators in depth. This study examines the interaction of education and wealth in relation to obesity, hypothesising that education protects against the obesogenic effect of wealth.
Four datasets of women of reproductive age from the Egyptian Demographic and Health Surveys spanning the period 1992–2008 are used to examine two distinct time periods: 1992/95 (N = 11097) and 2005/08 (N = 23178). The association in the two time periods between education level and household wealth in relation to the odds of being obese is examined, and the interaction between the two socioeconomic indicators investigated. Estimates are adjusted for age group and area of residence.
An interaction was found between the association of education and wealth with obesity in both time periods (P-value for interaction <0.001). For women with the lowest education level, moving up one wealth quintile was associated with a 78% increase in the odds of obesity in 1992/95 (OR; 95%CI: 1.78; 1.65,1.91) and a 33% increase in 2005/08 (OR; 95%CI: 1.33; 1.26,1.39). For women with the highest level of education, there was little evidence of an association between wealth and obesity (OR; 95%CI: 0.82; 0.57,1.16 in 1992/95 and 0.95; 0.84,1.08 in 2005/08). Obesity levels increased most in women who were in the no/primary education, poorest wealth quintile and rural groups (absolute difference in prevalence percentage points between the two time periods: 20.2, 20.1, and 21.3 respectively).
In the present study, wealth appears to be a risk factor for obesity in women with lower education levels, while women with higher education are protected. The findings also suggest that a reversal in the social distribution of obesity risk is occurring which can be explained by the large increase in obesity levels in lower socioeconomic groups between the two time periods.
PMCID: PMC3384649  PMID: 22761807
22.  PLA2G7 genotype, Lp-PLA2 activity and coronary heart disease risk in 10,494 cases and 15,624 controls of European ancestry 
Circulation  2010;121(21):2284-2293.
Higher Lp-PLA2 activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal.
Methods and Results
A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only and 2 cross-sectional, n=26,118) was undertaken to examine the association of: (i) LpPLA2 activity vs. cardiovascular biomarkers and risk factors and CHD events (two prospective studies; n=4884); ii) PLA2G7 SNPs and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and iii) PLA2G7 SNPs and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratio for CHD events top vs. bottom quartile of Lp-PLA2 activity was 1.61 (95%CI: 1.31, 1.99) and 1.17 (95%CI: 0.91, 1.51) after adjustment for baseline traits. Of seven SNPs, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (OR 1.03 (95%CI 0.80, 1.32), or CHD events (OR 0.98 (95%CI 0.82, 1.17).
Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma or CHD. Larger association studies, identification of SNPs with larger effects, or randomised trials of specific Lp-PLA2 inhibitors are needed to confirm/refute a contributory role for Lp-PLA2 in CHD.
PMCID: PMC3377948  PMID: 20479152
genetics; epidemiology; risk factors; Mendelian randomization
23.  The relationship between social network, social support and periodontal disease among older Americans 
The objectives of this study were to examine the relationship between social network, social support and periodontal disease among older American adults and to test whether social network and support mediates socioeconomic inequality in periodontal disease.
Materials and Methods
Data pertaining to participants aged 60 years and over from the National Health and Nutrition Examination Survey 2001-2004 was used. Periodontal disease variables were extent loss of periodontal attachment ≥ 3mm, and moderate periodontitis. Social support and networks were indicated by need for emotional support, number of close friends and marital status.
Widowed and those with lowest number of friends had higher rates of the extent of loss of periodontal attachment (1.27,95%CI:1.03,1.58) and (1.22,95%CI:1.03,1.45), respectively. Marital status and number of friends were not significantly associated with moderate periodontitis after adjusting for behavioural factors. The need for more emotional support was not related to periodontal disease in this analysis. Social networks and support had no impact on socioeconomic inequality in periodontal disease.
Certain aspects of social network, namely being widowed and having fewer friends were linked to the extent of loss of periodontal attachment but not to the definition of moderate periodontitis, in older adults.
PMCID: PMC3091988  PMID: 21362014
Periodontal disease; social network; social support; older adults
24.  Natural Course of Recurrent Psychological Distress in Adulthood 
Journal of affective disorders  2010;130(3):454-461.
The course of major depressive disorder is often characterized by progressing chronicity, but whether this applies to the course of self-reported psychological distress remains unclear. We examined whether the risk of self-reported psychological distress becomes progressively higher the longer the history of distress and whether prolonged history of distress modifies associations between risk markers and future distress.
Participants were British civil servants from the prospective Whitehall II cohort study (n=7934; 31.5% women, mean age 44.5 years at baseline) followed from 1985 to 2006 with repeat data collected in 7 study phases. Psychological distress was assessed with the 30-item General Health Questionnaire (GHQ). Sex, socioeconomic status, marital status, ethnicity, physical activity, alcohol consumption, smoking, and obesity were assessed as risk markers.
Recurrent history of psychological distress was associated with a progressively increasing risk of future distress in a dose-response manner. Common risk markers, such as low socioeconomic status, non-White ethnicity, being single, and alcohol abstinence were stronger predictors of subsequent distress in participants with a longer history of psychological distress. Sex differences in psychological distress attenuated with prolonged distress history.
The participants were already adults in the beginning of the study, so we could not assess the progressive chronicity of psychological distress from adolescence onwards.
These data suggest that self-reported psychological distress becomes more persistent over time and that a longer prior exposure to psychological distress increases sensitivity to the stressful effects of certain risk markers.
PMCID: PMC3062710  PMID: 21106248
Chronic distress; Kindling hypothesis; Longitudinal; Recurrence
25.  Height loss and future coronary heart disease in London: the Whitehall II study 
While several plausible biological mechanisms have been advanced for the association between greater physical stature and lower coronary heart disease (CHD) risk in prospective cohort studies, the importance of one of the principal artifactua explanations – reverse causality due to shrinkage – remains unresolved. To explore this issue, studies with repeat measurements of height are required, however, to date, such data have been lacking.
We analysed data from the Whitehall II prospective cohort study of 3802 men and 1615 women who participated in a physical examination in 1985/88, had their height re-measured in 1997/99, and were then followed for fatal and non-fatal CHD.
A mean follow-up of 7.4 years after the second height measurement gave rise to 69 CHD events in men (18 in women). After adjustment for baseline CHD risk factors, greater loss of physical stature between survey and resurvey was associated with an increased risk of CHD in men (hazard ratio; 95% CI for a one SD increase: 1.24; 1.00, 1.53) but not women (0.93; 0.58, 1.50).
It is possible that reverse causality due to shrinkage may contribute to the inverse association between a single measurement of height and later CHD in other studies.
PMCID: PMC3226938  PMID: 20805197

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