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1.  Job Strain as a Risk Factor for Type 2 Diabetes: A Pooled Analysis of 124,808 Men and Women 
Diabetes Care  2014;37(8):2268-2275.
The status of psychosocial stress at work as a risk factor for type 2 diabetes is unclear because existing evidence is based on small studies and is subject to confounding by lifestyle factors, such as obesity and physical inactivity. This collaborative study examined whether stress at work, defined as “job strain,” is associated with incident type 2 diabetes independent of lifestyle factors.
We extracted individual-level data for 124,808 diabetes-free adults from 13 European cohort studies participating in the IPD-Work Consortium. We measured job strain with baseline questionnaires. Incident type 2 diabetes at follow-up was ascertained using national health registers, clinical screening, and self-reports. We analyzed data for each study using Cox regression and pooled the study-specific estimates in fixed-effect meta-analyses.
There were 3,703 cases of incident diabetes during a mean follow-up of 10.3 years. After adjustment for age, sex, and socioeconomic status (SES), the hazard ratio (HR) for job strain compared with no job strain was 1.15 (95% CI 1.06–1.25) with no difference between men and women (1.19 [1.06–1.34] and 1.13 [1.00–1.28], respectively). In stratified analyses, job strain was associated with an increased risk of diabetes among those with healthy and unhealthy lifestyle habits. In a multivariable model adjusted for age, sex, SES, and lifestyle habits, the HR was 1.11 (1.00–1.23).
Findings from a large pan-European dataset suggest that job strain is a risk factor for type 2 diabetes in men and women independent of lifestyle factors.
PMCID: PMC4113178  PMID: 25061139
2.  Psychological Distress and Incidence of Type 2 Diabetes in High-Risk and Low-Risk Populations: The Whitehall II Cohort Study 
Diabetes Care  2014;37(8):2091-2097.
We examined whether psychological distress predicts incident type 2 diabetes and if the association differs between populations at higher or lower risk of type 2 diabetes.
This was a prospective cohort of 5,932 diabetes-free adults (4,189 men and 1,743 women, mean age 54.6 years) with three 5-year data cycles (1991–2009): a total of 13,207 person-observations. Participants were classified into four groups according to their prediabetes status and Framingham Offspring Type 2 Diabetes Risk Score: normoglycemia with a risk score of 0–9, normoglycemia with a risk score of 10–19, prediabetes with a risk score of 10–19, and prediabetes with a risk score of >19. Psychological distress was assessed by the General Health Questionnaire. Incident type 2 diabetes was ascertained by 2-h oral glucose tolerance test, doctor diagnosis, or use of antihyperglycemic medication at the 5-year follow-up for each data cycle. Adjustments were made for age, sex, ethnicity, socioeconomic status, antidepressant use, smoking, and physical activity.
Among participants with normoglycemia and among those with prediabetes combined with a low risk score, psychological distress did not predict type 2 diabetes. Diabetes incidence in these groups varied between 1.6 and 15.6%. Among participants with prediabetes and a high risk score, 40.9% of those with psychological distress compared with 28.5% of those without distress developed diabetes during the follow-up. The corresponding adjusted odds ratio for psychological distress was 2.07 (95% CI 1.19–3.62).
These data suggest that psychological distress is associated with an accelerated progression to manifest diabetes in a subpopulation with advanced prediabetes.
PMCID: PMC4113169  PMID: 24784831
3.  Change in sleep duration and type 2 diabetes: the Whitehall II study 
Diabetes care  2015;38(8):1467-1472.
Evidence suggests that short and long sleep are associated with a higher risk of type 2 diabetes. Using successive data waves spanning more than 20 years we examined whether a change in sleep duration is associated with incident diabetes.
Research Design and Methods
Sleep duration was reported at the beginning and end of four 5-year cycles: 1985-88 to 1991-94 (N=5613); 1991-94 to 1997-99 (N=4193); 1997-99 to 2002-04 (N=3840); 2002-04 to 2007-09 (N=4195). At each cycle, change in sleep duration was calculated for participants without diabetes. Incident diabetes at the end of the subsequent 5-year period was defined using: (1) fasting glucose; (2) 75g oral glucose tolerance test; and (3) glycated hemoglobin, in conjunction with diabetes medication and self-reported doctor diagnosis.
Compared to the reference group of persistent 7-hour sleepers, an increase of ≥2hours sleep per night was associated with a higher risk of incident diabetes; Odds Ratios (95% Confidence Intervals) 1.65 (95% CI: 1.15, 2.37), in analyses adjusted for age, sex, employment grade and ethnic group. This association was partially attenuated by adjustment for body mass index and change in weight; 1.50 (1.04, 2.16). An increased risk of incident diabetes was also seen in persistent short sleepers (average ≤5.5 hours/night); 1.35 (1.04, 1.76), but this evidence weakened on adjustment for body mass index and change in weight; 1.25 (0.96, 1.63).
This study suggests that individuals whose sleep duration increases are at an increased risk of type 2 diabetes. Greater weight and weight gain in this group partly explain the association.
PMCID: PMC4512137  PMID: 26068863
4.  Influence of Retirement on Adherence to Statins in the Insurance Medicine All-Sweden Total Population Data Base 
PLoS ONE  2015;10(6):e0130901.
Retirement has been suggested to reduce medication adherence, but no evidence is available for statins. We investigated changes in adherence to statins among Swedish adults after retirement.
A prospective cohort study was carried out on all individuals living in Sweden on 31 December 2004, alive in 2010, having purchased statins in the second half of 2005, and retired in 2008 (n=11 718). We used prescription dispensing data in 2006–2010 to determine nonadherence (defined as <80% of days covered by filled prescriptions) before and after old-age or disability retirement. Using multiple repeat measurements of filled statin prescriptions, we calculated the annual prevalence rates of nonadherence for those who continued therapy. Discontinuation was defined as no statin dispensations during a calendar year.
After adjustment for age at retirement, the prevalence ratio (PR) of nonadherence after retirement in comparison with those before retirement was 1.23 [95% confidence interval (CI) 1.17–1.29] for the men and 1.19 (95% CI 1.13–1.26) for the women. A post-retirement increase in nonadherence was consistently observed across the strata of age at retirement, marital status, education, income, type of retirement, and participants with and without cardiovascular disease, the largest increases being observed for statin use in secondary prevention (men: PR 1.38, 95% CI 1.26–1.54; women: PR 1.43, 1.18–1.72). For primary prevention, the corresponding prevalence ratios were 1.18 (95% CI 1.13‒1.25) and 1.18 (95% CI 1.11–1.24), respectively.
Retirement appears to be associated with increased nonadherence to statin therapy among Swedish men and women.
PMCID: PMC4477901  PMID: 26102521
5.  Childhood Adversity as a Predictor of Non-Adherence to Statin Therapy in Adulthood 
PLoS ONE  2015;10(5):e0127638.
To investigate whether adverse experiences in childhood predict non-adherence to statin therapy in adulthood.
A cohort of 1378 women and 538 men who initiated statin therapy during 2008–2010 after responding to a survey on childhood adversities, was followed for non-adherence during the first treatment year. Log-binomial regression was used to estimate predictors of non-adherence, defined as the proportion of days covered by dispensed statin tablets <80%. In fully adjusted models including age, education, marital status, current smoking, heavy alcohol use, physical inactivity, obesity, presence of depression and cardiovascular comorbidity, the number of women ranged from 1172 to 1299 and that of men from 473 to 516, because of missing data on specific adversities and covariates.
Two in three respondents reported at least one of the following six adversities in the family: divorce/separation of the parents, long-term financial difficulties, severe conflicts, frequent fear, severe illness, or alcohol problem of a family member. 51% of women and 44% of men were non-adherent. In men, the number of childhood adversities predicted an increased risk of non-adherence (risk ratio [RR] per adversity 1.11, 95% confidence interval [CI] 1.01–1.21], P for linear trend 0.013). Compared with those reporting no adversities, men reporting 3–6 adversities had a 1.44-fold risk of non-adherence (95% CI 1.12–1.85). Experiencing severe conflicts in the family (RR 1.27, 95% CI 1.03–1.57]) and frequent fear of a family member (RR 1.27, 95% CI 1.00–1.62]) in particular, predicted an increased risk of non-adherence. In women, neither the number of adversities nor any specific type of adversity predicted non-adherence.
Exposure to childhood adversity may predict non-adherence to preventive cardiovascular medication in men. Usefulness of information on childhood adversities in identification of adults at high risk of non-adherence deserves further research.
PMCID: PMC4444303  PMID: 26011609
6.  Interarm Differences in Systolic Blood Pressure and Mortality Among US Army Veterans: Aetiological Associations and Risk Prediction in the Vietnam Experience Study 
Differences between the arms in systolic blood pressure [SBP] of ≥10 mm Hg have been associated with an increased risk of mortality in patients with hypertensive and chronic renal disease. For the first time, we examined these relationships in a non-clinical population.
Cohort study.
Participants were 4419 men [mean age, 38.37] from the Vietnam Experience Study. Bilateral SBP and diastolic BP [DBP], serum lipids, fasting glucose, erythrocyte sedimentation rate [ESR], metabolic syndrome, and ankle brachial index were assessed in 1986.
Ten percent of men had an interarm difference of ≥10 and 2.4% of ≥15 mmHg. A 15-year follow-up period gave rise to 246 deaths [64 from cardiovascular disease [(CVD)]. Interarm differences of ≥10 mm Hg were associated with an elevated risk of all-cause [hazard ratio (HR) = 1.49, 95% confidence interval (CI), 1.04 – 2.14] and CVD mortality [HR = 1.93, 95% CI, 1.01 – 3.69]. After adjusting for SBP, DBP, lipids, fasting glucose and ESR, associations between interarm differences of ≥10 mm Hg and all-cause (HR=1.35, 95% CI = 0.94 – 1.95) and CVD mortality (HR = 1.62, 95% CI, 0.84 - 3.14) were significantly attenuated.
In this non-clinical cohort study, interarm differences in SBP were not associated with mortality after accounting for traditional CVD risk factors. Interarm differences might not be valuable as an additional risk factor for mortality in populations with a low risk of CVD.
PMCID: PMC3805466  PMID: 23818287
Epidemiology; Risk Factors; Hypertension
7.  The Authors Reply 
American Journal of Epidemiology  2014;179(6):792-793.
PMCID: PMC3939854  PMID: 24738124
8.  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
9.  Socioeconomic and Psychosocial Adversity in Midlife and Depressive Symptoms Post Retirement: A 21-year Follow-up of the Whitehall II Study 
We examined whether socioeconomic and psychosocial adversity in midlife predicts post-retirement depressive symptoms.
Design and Setting
A prospective cohort study of British civil servants who responded to a self-administered questionnaire in middle-age and at older ages, 21 years later.
The study sample consisted of 3,939 Whitehall II Study participants (2,789 men, 1,150 women; mean age 67.6 years at follow-up) who were employed at baseline and retired at follow-up.
Midlife adversity was assessed by self-reported socioeconomic adversity (low occupational position; poor standard of living) and psychosocial adversity (high job strain; few close relationships). Symptoms of depression post-retirement were measured by the Center for Epidemiologic Studies Depression scale.
After adjustment for sociodemographic and health-related covariates at baseline and follow-up, there were strong associations between midlife adversities and post-retirement depressive symptoms: low occupational position (odds ratio [OR]: 1.70, 95% confidence interval [CI]: 1.15–2.51), poor standard of living (OR: 2.37, 95% CI: 1.66–3.39), high job strain (OR: 1.52, 95% CI: 1.09–2.14), and few close relationships (OR: 1.51, 95% CI: 1.12–2.03). The strength of the associations between socioeconomic, psychosocial, work-related, or non-work related exposures and depressive symptoms was similar.
Robust associations from observational data suggest that several socioeconomic and psychosocial risk factors for symptoms of depression post-retirement can be detected already in midlife.
PMCID: PMC4270962  PMID: 24816123
Depression; elderly; inequalities; life course; mood disorders; old age; prospective; stress
10.  Long working hours, socioeconomic status, and the risk of incident type 2 diabetes: a meta-analysis of published and unpublished data from 222 120 individuals 
Working long hours might have adverse health effects, but whether this is true for all socioeconomic status groups is unclear. In this meta-analysis stratified by socioeconomic status, we investigated the role of long working hours as a risk factor for type 2 diabetes.
We identified four published studies through a systematic literature search of PubMed and Embase up to April 30, 2014. Study inclusion criteria were English-language publication; prospective design (cohort study); investigation of the effect of working hours or overtime work; incident diabetes as an outcome; and relative risks, odds ratios, or hazard ratios (HRs) with 95% CIs, or sufficient information to calculate these estimates. Additionally, we used unpublished individual-level data from 19 cohort studies from the Individual-Participant-Data Meta-analysis in Working-Populations Consortium and international open-access data archives. Effect estimates from published and unpublished data from 222 120 men and women from the USA, Europe, Japan, and Australia were pooled with random-effects meta-analysis.
During 1·7 million person-years at risk, 4963 individuals developed diabetes (incidence 29 per 10 000 person-years). The minimally adjusted summary risk ratio for long (≥55 h per week) compared with standard working hours (35–40 h) was 1·07 (95% CI 0·89–1·27, difference in incidence three cases per 10 000 person-years) with significant heterogeneity in study-specific estimates (I2=53%, p=0·0016). In an analysis stratified by socioeconomic status, the association between long working hours and diabetes was evident in the low socioeconomic status group (risk ratio 1·29, 95% CI 1·06–1·57, difference in incidence 13 per 10 000 person-years, I2=0%, p=0·4662), but was null in the high socioeconomic status group (1·00, 95% CI 0·80–1·25, incidence difference zero per 10 000 person-years, I2=15%, p=0·2464). The association in the low socioeconomic status group was robust to adjustment for age, sex, obesity, and physical activity, and remained after exclusion of shift workers.
In this meta-analysis, the link between longer working hours and type 2 diabetes was apparent only in individuals in the low socioeconomic status groups.
Medical Research Council, European Union New and Emerging Risks in Occupational Safety and Health research programme, Finnish Work Environment Fund, Swedish Research Council for Working Life and Social Research, German Social Accident Insurance, Danish National Research Centre for the Working Environment, Academy of Finland, Ministry of Social Affairs and Employment (Netherlands), Economic and Social Research Council, US National Institutes of Health, and British Heart Foundation.
PMCID: PMC4286814  PMID: 25262544
11.  Age trajectories of glycaemic traits in non-diabetic South Asian and white individuals: the Whitehall II cohort study 
Diabetologia  2014;58:534-542.
South Asian individuals have an increased prevalence of type 2 diabetes, but little is known about the development of glycaemic traits in this ethnic group. We compared age-related changes in glycaemic traits between non-diabetic South Asian and white participants.
In a prospective British occupational cohort with 5-yearly clinical examinations (n = 230/5,749 South Asian/white participants, age 39–79 years at baseline), age-related trajectories of fasting glucose (FG) and 2 h post-load glucose (PLG), log-transformed fasting insulin (FINS) and 2 h post-load insulin (PLINS), HOMA insulin sensitivity (HOMA2-%S) and HOMA insulin secretion (HOMA2-%B) were fitted for South Asian and white individuals who remained free of diabetes between 1991 and 2009.
In sex-adjusted multilevel models, FG was stable in white participants but increased with age in South Asians (0.12 [SE = 0.04] mmol/l per decade). PLG, FINS and PLINS levels were lower among white participants (by 0.271 [SE = 0.092] mmol/l, 0.306 [SE = 0.046] log pmol/l, 0.707 [SE = 0.059] log pmol/l at age 50, respectively) compared with South Asians, although their age-related trajectories were parallel. HOMA2-%S was higher (0.226 [SE = 0.038] at age 50) and HOMA2-%B lower (by 0.189 [SE = 0.026] at age 50) among white than South Asian participants. The age-related decline in HOMA2-%S was similar in these groups, but the age-related increase in HOMA2-%B was greater in white participants (0.04 [SE = 0.02] per decade). This difference was explained by obesity, lifestyle and social status.
Findings from a diabetes-free population suggest an inadequate pancreatic beta cell reserve in South Asians, as a significantly steeper age-related increase in FG was observed in this ethnic group compared with white individuals.
PMCID: PMC4320303  PMID: 25431266
Cohort study; Ethnicity; Fasting glucose; Fasting insulin; Glycaemic trajectory; Insulin resistance; Insulin secretion; Insulin sensitivity; Post-load glucose; South Asian
12.  Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: population-based study 
European Heart Journal  2013;34(38):2933-2939.
Antihypertensive drug therapy is a major strategy of stroke prevention among hypertensive patients. The aim of this study was to estimate the excess risk of stroke associated with non-adherence to antihypertensive drug therapy among hypertensive patients.
Methods and results
We conducted a population-based study using records from Finnish national registers for 1 January 1995 to 31 December 2007. Of the 73 527 hypertensive patients aged 30 years or older and without pre-existing stroke or cardiovascular disease, 2144 died from stroke and 24 560 were hospitalized due to stroke during the follow-up. At the 2- and 10-year follow-up after the start of continuous antihypertensive medication, non-adherent patients had 3.81 [95% confidence interval (CI) 2.85–5.10] and 3.01 (95% CI: 2.37–3.83) times higher odds of stroke death when compared with the adherent patients. The corresponding odds ratio (OR) for stroke hospitalization was 2.74 (95% CI: 2.35–3.20) at Year 2 and 1.71 (95% CI: 1.49–1.96) at Year 10. In the stroke-event year, the ORs were higher, 5.68 (95% CI: 5.05–6.39) for stroke death and 1.87 (95% CI: 1.72–2.03) for hospitalization. Among those using agents acting on the renin–angiotensin system combined with diuretics or β-blockers, these ORs were 7.49 (95% CI: 5.62–9.98) and 3.91 (95% CI: 3.23–4.75), respectively. The associations between non-adherence and stroke followed a dose–response pattern—the poorer the adherence, the greater the risk of death and hospitalization due to stroke.
These data suggest that poor adherence to antihypertensive therapy substantially increases near- and long-term risk of stroke among hypertensive patients.
PMCID: PMC3791393  PMID: 23861328
Adherence; Antihypertensive therapy; Stroke; Hypertension; Mortality
13.  Association between protein signals and type 2 diabetes incidence 
Acta diabetologica  2012;50(5):697-704.
Understanding early determinants of type 2 diabetes is essential for refining disease prevention strategies. Proteomic technology may provide a useful approach to identify novel protein patterns potentially related to pathophysiological changes that lead up to diabetes. In this study, we sought to identify protein signals that are associated with diabetes incidence in a middle-aged population. Serum samples from 519 participants in a nested case–control selection (167 cases and 352 age-, sex- and BMI-matched normoglycemic control subjects, median follow-up 14.0 years) within the Whitehall-II cohort were analyzed by linear matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Nine protein peaks were found to be associated with incident diabetes. Rate ratios for high peak intensity ranged between 0.4 (95% CI, 0.2–0.8) and 4.0 (95% CI, 1.7–9.2) and were robust to adjustment for main potential confounders, including obesity, lipids and C-reactive protein. The proteins associated with these peaks may reflect diabetes pathogenesis. Our study exemplifies the utility of an approach that combines proteomic and epidemiological data.
PMCID: PMC4181558  PMID: 22310914
MALDI-TOF; Type 2 diabetes; Proteomics; Biomarker; Whitehall-II study; Random Forests
14.  Informal Caregiving and the Risk for Coronary Heart Disease: The Whitehall II Study 
The stress associated with informal caregiving has been shown to be associated with poor health, including coronary heart disease (CHD). However, it is unclear if the risk of CHD is attributable to caregiving or prior poor health of the caregiver.
We used data from the Whitehall II cohort study. Caregiving and caregiver’s health (using 3 measures: self-rated health, mental health using the General Health Questionnaire, and physical component score of the SF-36) were assessed in 1991–1993 among 5,468 men and 2,457 women aged 39–63 years. CHD (fatal CHD, clinically verified nonfatal myocardial infarction, and definite angina) incidence was recorded for a mean 17 years; sociodemographic variables, health behaviors, and cardiovascular risk factors were included as covariates.
Cox regression showed the risk of CHD in caregivers not to be higher (hazard ratio = 1.18; 95% CI: 0.96, 1.45) compared with noncaregivers. Analyses stratified by health status showed that compared with noncaregivers in good health, caregivers with poor self-rated (hazard ratio = 2.00; 95% CI: 1.44, 2.78), mental (hazard ratio = 1.63; 95% CI: 1.16, 2.30), or physical (hazard ratio =1.87; 95% CI: 1.34, 2.62) health had greater risk of CHD. A similar elevated risk was observed in noncaregivers with poor health; no excess risk was observed among caregivers reporting good health, and the combined effect of poor health and caregiving did not exceed their independent effects.
Caregiving in midlife is not in itself associated with greater risk of CHD, but it is associated with increased risk for CHD among caregivers who report being in poor health.
PMCID: PMC3779628  PMID: 23525476
Coronary heart disease; Stress; Caregiver.
15.  Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study 
European journal of epidemiology  2012;27(7):537-546.
Although it has been hypothesized that the association of physical activity with depressive and anxiety symptoms is bidirectional, few studies have examined this issue in a prospective setting. We studied this bidirectional association using data on physical activity and symptoms of anxiety and depression at three points in time over 8 years. A total of 9,309 participants of the British Whitehall II prospective cohort study provided data on physical activity, anxiety and depression symptoms and 10 covariates at baseline in 1985. We analysed the associations of physical activity with anxiety and/or depression symptoms using multinomial logistic regression (with anxiety and depression symptoms as dependent variables) and binary logistic regression (with physical activity as the dependent variable). There was a cross-sectional inverse association between physical activity and anxiety and/or depressive symptoms at baseline (ORs between 0.63 and 0.72). In cumulative analyses, regular physical activity across all three data waves, but not irregular physical activity, was associated with reduced likelihood of depressive symptoms at follow-up (OR = 0.71, 95 % CI 0.54, 0.99). In a converse analysis, participants with anxiety and depression symptoms at baseline had higher odds of not meeting the recommended levels of physical activity at follow-up (OR = 1.79, 95 % CI 1.17, 2.74). This was also the case in individuals with anxiety and/or depression symptoms at both baseline and follow-up (OR = 1.70, 95 % CI 1.10, 2.63). The association between physical activity and symptoms of anxiety and/or depression appears to be bidirectional.
PMCID: PMC4180054  PMID: 22623145
Common mental disorders; Physical activity; Bidirectional association; Longitudinal studies
16.  Self-Rated Health in the Last 12 Years of Life Compared to Matched Surviving Controls: The Health and Retirement Study 
PLoS ONE  2014;9(9):e107879.
Self-rated health (SRH) is a valid measure of health status and associated with mortality. Based on individual-level biannual repeat data on SRH we sought to characterize the natural history of poor SRH during the 12 years prior to death in men and women in different age groups. We conducted a retrospective analysis of the Health and Retirement Study participants who died between 1998 and 2010 and had at least two SRH measurements in the 12 years prior to death. We used a nested case-control design to compare SRH trajectories of deceased men and women aged 30–64, 65–79 and 80 years versus surviving participants. The cases comprised 3,350 deceased participants who were matched to surviving controls (n = 8,127). SRH was dichotomized into good vs. poor health. Men and women dying at age 65–79 and ≥80 years had 1.5 to 3 times higher prevalence of poor SRH already 11–12 years prior to death compared to surviving controls. The risk estimates remained statistically significant even after adjusting for life-style related risk factors and diagnosed diseases. Prevalence of poor SRH before death was lowest among those aged ≥80 years and highest in 30–64 year-olds. In conclusion, men and women who subsequently die perceive their health worse already 11–12 years prior to death compared to their surviving controls.
PMCID: PMC4169624  PMID: 25237814
17.  The Authors Reply 
American Journal of Epidemiology  2013;178(6):1009-1010.
PMCID: PMC3775548  PMID: 24171205
18.  Associations Between Change in Sleep Duration and Inflammation: Findings on C-reactive Protein and Interleukin 6 in the Whitehall II Study 
American Journal of Epidemiology  2013;178(6):956-961.
Cross-sectional evidence suggests associations between sleep duration and levels of the inflammatory markers, C-reactive protein and interleukin-6. This longitudinal study uses data from the London-based Whitehall II study to examine whether changes in sleep duration are associated with average levels of inflammation from 2 measures 5 years apart. Sleep duration (≤5, 6, 7, 8, ≥9 hours on an average week night) was assessed in 5,003 middle-aged women and men in 1991/1994 and 1997/1999. Fasting levels of C-reactive protein and interleukin-6 were measured in 1997/1999 and 2002/2004. Cross-sectional analyses indicated that shorter sleep is associated with higher levels of inflammatory markers. Longitudinal analyses showed that each hour per night decrease in sleep duration between 1991/1994 and 1997/1999 was associated with higher levels of C-reactive protein (8.1%) and interleukin-6 (4.5%) averaged across measures in 1997/1999 and 2002/2004. Adjustment for longstanding illness and major cardiometabolic risk factors indicated that disease processes may partially underlie these associations. An increase in sleep duration was not associated with average levels of inflammatory markers. These results suggest that both short sleep and reductions in sleep are associated with average levels of inflammation over a 5-year period.
PMCID: PMC3817449  PMID: 23801012
change in sleep duration; C-reactive protein; inflammatory markers; interleukin-6; sleep duration
19.  Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study 
European Heart Journal  2013;34(34):2697-2705.
Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact.
Methods and results
Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health ‘a lot or extremely’ had a 2.12 times higher (95% CI 1.52–2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01–2.22).
In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health.
PMCID: PMC3766148  PMID: 23804585
Epidemiology; Stress; Coronary heart disease; Prospective studies
20.  Vertical and Horizontal Trust at Work as Predictors of Retirement Intentions: The Finnish Public Sector Study 
PLoS ONE  2014;9(9):e106956.
This prospective cohort study aimed to examine the associations of trust towards the supervisor (vertical trust) and trust towards co-workers (horizontal trust) with retirement intentions. The participants were 14 840 women and men working in the municipal sector in 2000–12 (Finnish Public Sector Study). Trust (vertical trust towards the supervisor and horizontal trust towards co-workers) and retirement intentions were assessed in repeated surveys. Multivariable multinomial logistic regression analyses were conducted to assess the association between baseline trust and retirement intentions at 3.7 years of follow-up. Demographic characteristics, health, psychological distress, health risk behaviors, personality factors, and psychosocial factors were included as covariates. Of the participants, 67.0% trusted their supervisor and 54.9% trusted their co-workers. Employees who trusted their supervisor (odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67) and employees who trusted their co-workers (odds ratio 0.62, 95% confidence interval 0.55–0.70) at baseline were less likely to have strong retirement intentions at follow-up compared to those who did not trust. These associations largely persisted after adjusting for all covariates and taking into account baseline retirement intentions. In conclusion, trust in the supervisor and co-workers predicted retirement intentions. These observational findings suggest that increasing trust in the workplace may contribute to lengthening working careers and preventing early retirement.
PMCID: PMC4156392  PMID: 25191745
21.  Lifestyle factors as predictors of nonadherence to statin therapy among patients with and without cardiovascular comorbidities 
Easily detectable predictors of nonadherence to long-term drug treatment are lacking. We investigated the association between lifestyle factors and nonadherence to statin therapy among patients with and without cardiovascular comorbidities.
We included 9285 participants from the Finnish Public Sector Study who began statin therapy after completing the survey. We linked their survey data with data in national health registers. We used prescription dispensing data to determine participants’ nonadherence to statin therapy during the first year of treatment (defined as < 80% of days covered by filled prescriptions). We used logistic regression to estimate the association of several lifestyle factors with nonadherence, after adjusting for sex, age and year of statin initiation.
Of the participants without cardiovascular comorbidities (n = 6458), 3171 (49.1%) were nonadherent with their statin therapy. Obesity (adjusted odds ratio [OR] 0.86, 95% confidence interval [CI] 0.74–0.99), overweight (adjusted OR 0.88, 95% CI 0.79–0.98) and former smoking (adjusted OR 0.82, 95% CI 0.74–0.92) predicted a reduced risk of nonadherence in this group after adjustment for sex, age and year of statin initiation. Of the participants with cardiovascular comorbidities (n = 2827), 1155 (40.9%) were nonadherent. In this group, high alcohol consumption (adjusted OR 1.55, 95% CI 1.12–2.15), extreme drinking occasions (adjusted OR 1.48, 95% CI 1.11–1.97) and a cluster of 3–4 lifestyle risks (adjusted OR 1.61, 95% CI 1.15–2.27) predicted increased odds of nonadherence after adjustment for sex, age and year of statin initiation.
People with cardiovascular comorbidities who had risky drinking behaviours or a cluster of lifestyle risks were at increased risk of nonadherence. Among individuals without cardiovascular comorbidities, information on lifestyle factors was unhelpful in identifying those at increased risk of nonadherence; that overweight, obesity and former smoking were predictors of better adherence in this group provides insight into mechanisms of adherence to preventive medication that deserve further study.
PMCID: PMC4150731  PMID: 24958839
22.  Midlife stroke risk and cognitive decline: A 10-year follow-up of the Whitehall II cohort study 
Stroke is associated with an increased risk of dementia. However, it is unclear if risk of stroke in those free of stroke, particularly in non-elderly populations, leads to differential rates of cognitive decline. Our aim was to assess whether risk of stroke in midlife was associated with cognitive decline over 10 years of follow-up.
We studied 4,153 men and 1,657 women, mean age 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We used the Framingham Stroke Risk Profile (FSRP) that incorporates age, systolic blood pressure, diabetes mellitus, smoking, prior cardiovascular disease, atrial fibrillation, left ventricular hypertrophy, and use of antihypertensive medication. Cognitive tests included reasoning, memory, verbal fluency, and vocabulary assessed three times over ten years. Longitudinal associations between FSRP and its components were tested using mixed effects models and rates of cognitive change over 10 years were estimated.
Higher stroke risk was associated with faster decline in verbal fluency, vocabulary and global cognition. For example, for global cognition there was greater decline in the highest FSRP quartile (−0.25 of a standard deviation; 95% CI: −0.28 to −0.21) compared to the lowest risk quartile (P=0.03). No association was observed for memory and reasoning. Of the individual components of FSRP only diabetes was independently associated with faster cognitive decline (β=−0.06; 95% CI:−0.01, −0.003, P=0.03).
Elevated stroke risk is associated with accelerated cognitive decline over 10 years. Aggregation of risk factors may be especially important in this association.
PMCID: PMC3918666  PMID: 23199495
vascular risk factors; cognitive decline; Framingham Stroke Risk Profile; aging; midlife
23.  Proximity of off-premise alcohol outlets and heavy alcohol consumption: A cohort study* 
Drug and alcohol dependence  2013;132(0):295-300.
Availability of alcohol has been associated with alcohol consumption in cross-sectional studies. We examined longitudinally whether change in proximity to off-premise (i.e., no consumption on the premises) beer and liquor outlets is associated with heavy alcohol consumption.
Distances from 54,778 Finnish Public Sector study participants' homes to the nearest off-premise beer and liquor outlets were calculated using Global Positioning System-coordinates. Between-individual analyses were used to study the effects of distance to the nearest outlet on heavy alcohol use, and within-individual analyses to study the effects of a change in distance on change in heavy use.
Mean follow-up time in 2000–2009 was 6.8 (standard deviation 2.0) years. In a between-individual analysis, decrease from ≥500m to <500m (vs. remained ≥500m) in the distance to the nearest beer outlet increased the likelihood of incident heavy alcohol use in women (odds ratio 1.23, 95% CI 1.05–1.44), but not in men. In a within-individual analysis decrease from 500m to 0m in log-transformed continuous distance to the nearest beer outlet increased the odds of heavy alcohol consumption in women by 13% (odds ratio 1.13, 95% CI 1.01–1.27). For the corresponding change in distance to liquor outlet the increase was 3% (odds ratio 1.03, 95% CI 0.97–1.09).
Change in distance from home to the nearest off-premise alcohol outlet affects the risk of heavy alcohol consumption in women. This evidence supports policies that restrict physical availability of alcohol.
PMCID: PMC3709004  PMID: 23499055
alcohol consumption; alcohol policy; availability; distance; longitudinal; Finnish Public Sector Study
24.  Personality and All-Cause Mortality: Individual-Participant Meta-Analysis of 3,947 Deaths in 76,150 Adults 
American Journal of Epidemiology  2013;178(5):667-675.
Personality may influence the risk of death, but the evidence remains inconsistent. We examined associations between personality traits of the five-factor model (extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience) and the risk of death from all causes through individual-participant meta-analysis of 76,150 participants from 7 cohorts (the British Household Panel Survey, 2006–2009; the German Socio-Economic Panel Study, 2005–2010; the Household, Income and Labour Dynamics in Australia Survey, 2006–2010; the US Health and Retirement Study, 2006–2010; the Midlife in the United States Study, 1995–2004; and the Wisconsin Longitudinal Study's graduate and sibling samples, 1993–2009). During 444,770 person-years at risk, 3,947 participants (54.4% women) died (mean age at baseline = 50.9 years; mean follow-up = 5.9 years). Only low conscientiousness—reflecting low persistence, poor self-control, and lack of long-term planning—was associated with elevated mortality risk when taking into account age, sex, ethnicity/nationality, and all 5 personality traits. Individuals in the lowest tertile of conscientiousness had a 1.4 times higher risk of death (hazard ratio = 1.37, 95% confidence interval: 1.18, 1.58) compared with individuals in the top 2 tertiles. This association remained after further adjustment for health behaviors, marital status, and education. In conclusion, of the higher-order personality traits measured by the five-factor model, only conscientiousness appears to be related to mortality risk across populations.
PMCID: PMC3755650  PMID: 23911610
meta-analysis; mortality; personality; psychology; survival analysis
25.  Genome-wide scan of job-related exhaustion with three replication studies implicate a susceptibility variant at the UST gene locus 
Human Molecular Genetics  2013;22(16):3363-3372.
Job-related exhaustion is the core dimension of burnout, a work-related stress syndrome that has several negative health consequences. In this study, we explored the molecular genetic background of job-related exhaustion. A genome-wide analysis of job-related exhaustion was performed in the GENMETS subcohort (n = 1256) of the Finnish population-based Health 2000 study. Replication analyses included an analysis of the strongest associations in the rest of the Health 2000 sample (n = 1660 workers) and in three independent populations (the FINRISK population cohort, n = 10 753; two occupational cohorts, total n = 1451). Job-related exhaustion was ascertained using a standard self-administered questionnaire (the Maslach Burnout Inventory (MBI)-GS exhaustion scale in the Health 2000 sample and the occupational cohorts) or a single question (FINRISK). A variant located in an intron of UST, uronyl-2-sulfotransferase (rs13219957), gave the strongest statistical evidence in the initial genome-wide study (P = 1.55 × 10−7), and was associated with job-related exhaustion in all the replication sets (P < 0.05; P = 6.75 × 10−7 from the meta-analysis). Consistent with studies of mood disorders, individual common genetic variants did not have any strong effect on job-related exhaustion. However, the nominally significant signals from the allelic variant of UST in four separate samples suggest that this variant might be a weak risk factor for job-related exhaustion. Together with the previously reported associations of other dermatan/chondroitin sulfate genes with mood disorders, these results indicate a potential molecular pathway for stress-related traits and mark a candidate region for further studies of job-related and general exhaustion.
PMCID: PMC3723313  PMID: 23620144

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