Evolution of genetic networks for human creativity.

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and chimpanzees in their numbers of genes for both self-control and self-awareness. 95% of the 267 genes we found only in modern humans were not protein-coding, including many long-non-coding RNAs in the self-awareness network. These genes may have arisen by positive selection for the characteristics of human well-being and behavioral modernity, including creativity, prosocial behavior, and healthy longevity. The genes that cluster in association with those found only in modern humans are over-expressed in brain regions involved in human self-awareness and creativity, including late-myelinating and phylogenetically recent regions of neocortex for autobiographical memory in frontal, parietal, and temporal regions, as well as related components of cortico-thalamo-ponto-cerebellar-cortical and cortico-striato-cortical loops. We conclude that modern humans have more than 200 unique non-protein-coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals.

Education as a moderator of genetic risk for higher body mass index: prospective cohort study from childhood to adulthood.

OBJECTIVES: The life-course development of body mass index (BMI) may be driven by interactions between genes and obesity-inducing social environments. We examined whether lower parental or own education accentuates the genetic risk for higher BMI over the life course, and whether diet and physical activity account for the educational differences in genetic associations with BMI. SUBJECTS/METHODS: The study comprised 2441 participants (1319 women, 3-18 years at baseline) from the prospective, population-based Cardiovascular Risk in Young Finns Study. BMI (kg/m2) trajectories were calculated from 18 to 49 years, using data from six time points spanning 31 years. A polygenic risk score for BMI was calculated as a weighted sum of risk alleles in 97 single-nucleotide polymorphisms. Education was assessed via self-reports, measured prospectively from participants in adulthood and from parents when participants were children. Diet and physical activity were self-reported in adulthood. RESULTS: Mean BMI increased from 22.6 to 26.6 kg/m2 during the follow-up. In growth curve analyses, the genetic risk score was associated with faster BMI increase over time (b=0.02, (95% CI, 0.01-0.02, P<0.001)). The association between the genetic risk score and BMI was more pronounced among those with lower educational level in adulthood (b=-0.12 (95% CI, -0.23-0.01); P=0.036)). No interaction effect was observed between the genetic risk score and parental education (b=0.05 (95% CI, -0.09-0.18; P=0.51)). Diet and physical activity explained little of the interaction effect between the genetic risk score and adulthood education. CONCLUSIONS: In this prospective study, the association of a risk score of 97 genetic variants with BMI was stronger among those with low compared with high education. This suggests lower education in adulthood accentuates the risk of higher BMI in people at genetic risk.

Work stress, poor recovery and burnout in teachers.

BACKGROUND: Both work stress and poor recovery have been shown to contribute to the development of burnout. However, the role of recovery as a mediating mechanism that links work stress to burnout has not been sufficiently addressed in research. AIMS: To examine recovery as a mediator in the relationship between work stress and burnout among teachers. METHODS: A cross-sectional study of Finnish primary school teachers, in whom burnout was measured with the Maslach Burnout Inventory-General Survey and work stress was conceptualized using the effort-reward imbalance (ERI) model. Recovery was measured with the Recovery Experience Questionnaire and the Jenkins Sleep Problems Scale. Multiple linear regression analyses and bootstrap mediation analyses adjusted for age, gender and total working hours were performed. RESULTS: Among the 76 study subjects, high ERI was associated with burnout and its dimensions of exhaustion, cynicism and reduced professional efficacy. Poor recovery experiences, in terms of low relaxation during leisure time, partially mediated the relationship between ERI and reduced professional efficacy. Sleep problems, in the form of non-restorative sleep, partially mediated the relationship between ERI and both burnout and exhaustion. CONCLUSIONS: Supporting a balance between effort and reward at work may enhance leisure time recovery and improve sleep quality, as well as help to reduce burnout rates.

Depressive symptoms are associated with lower bone mineral density in young adults with high job strain. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Job strain has been associated with depressive symptoms, and depression has been associated with low bone mineral density (BMD). PURPOSE: The associations between BMD and job strain have not been studied. We examined the relations between BMD, job strain, and depressive symptoms in a population-based group of young adults in Finland. METHOD: Ultrasonic measurement of BMD at the calcaneus was performed on 777 participants (men 45 %, aged 30-45) drawn from the Cardiovascular Risk in Young Finns Study. Job strain was assessed by self-administered questionnaires by the combination of job demands and job control. Depressive symptoms were assessed with a modified Beck Depression Inventory. The effects of job strain on BMD were studied with multivariable analyses with age, sex, BMI, vitamin D, and calcium intake, physical activity, cigarette smoking, alcohol use, and depressive symptoms as covariates. RESULTS: Depressive symptoms were independently associated with lower BMD T score in participants with high job strain (ß = -0.241, p = 0.02), but depressive symptoms were not significantly associated with BMD in the low (ß = -0.160, p = 0.26) and intermediate (ß = -0.042, p = 0.66) job strain categories. CONCLUSION: The results suggest that job strain modifies the association between depressive symptoms and BMD. Depressed individuals with high work-related stress might be in increased risk of lower bone mineral density.

Longitudinal course of depressive symptoms in adulthood: linear stochastic differential equation modeling.

BACKGROUND: Although many studies have addressed the topic of stability versus change in depressive symptoms, few have further decomposed the change to continuous accumulation versus non-systematic state fluctuations or measurement errors. This further step requires a longitudinal follow-up and an appropriate stochastic model; it would, for example, evaluate the hypothesis that women accumulate more susceptibility events than men. Method A linear stochastic differential equation model was estimated for a 16-year longitudinal course of depressive symptoms in the Young Finns community sample of 3596 participants (1832 women, 1764 men). This model enabled us to decompose the variance in depression symptoms into a stable trait, cumulative effects and state/error fluctuations. RESULTS: Women showed higher mean levels and higher variance of depressive symptoms than men. In men, the stable trait accounted for the majority [61%, 90% confidence interval (CI) 48.9-69.2] of the total variance, followed by cumulative effects (23%, 90% CI 9.9-41.7) and state/error fluctuations (16%, 90% CI 5.6-23.2). In women, the cumulative sources were more important than among men and accounted for 44% (90% CI 23.6-58.9) of the variance, followed by stable individual differences (32%, 90% CI 18.5-54.2) and state fluctuations (24%, 90% CI 19.1-27.3). CONCLUSIONS: The results are consistent with previous observations that women suffer more depression than men, and have more variance in depressive symptoms. We also found that continuously accumulating effects are a significant contributor to between-individual differences in depression, especially for women. Although the accumulating effects are often confounded with non-systematic state fluctuations, the latter are unlikely to exceed 27% of the total variance of depressive symptoms.

Childhood family factors predict developmental trajectories of hostility and anger: a prospective study from childhood into middle adulthood.

BACKGROUND: Low socio-economic status (SES), and a conflictive, cold and unsupportive family environment in childhood have been associated with early adulthood hostility. However, it is unknown whether this association changes in magnitude with age from childhood to adulthood. We investigated whether childhood family factors (SES and parental child-rearing style) predicted differential development of offspring hostility and anger from early to middle adulthood. METHOD: Between 2041 and 2316 participants (age range 3-18 years at baseline) were selected from the longitudinal Young Finns study. The participants were followed for 27 years between 1980 and 2007. Childhood SES and parent's self-reported child-rearing style were measured twice: at baseline and 3 years after baseline. Hostility and anger were assessed with self-report questionnaires at 12, 17, 21 and 27 years after baseline. RESULTS: Low parental SES and hostile child-rearing style at baseline predicted higher mean levels of offspring anger and hostility. Low parental SES and one of the hostile child-rearing style components (strict disciplinary style) became more strongly associated with offspring hostility with age, suggesting an accumulating effect. CONCLUSIONS: Childhood family factors predict the development of hostility and anger over 27 years and some of these family factors have a long-term accumulating effect on the development of hostility.

Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort.

BACKGROUND: The psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension 'harm avoidance' (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT) density in vivo with positron emission tomography (PET) in healthy individuals with high or low HA scores using an 'oversampling' study design. Method Subjects consistently in either upper or lower quartiles for the HA trait were selected from a population-based cohort in Finland (n = 2075) with pre-existing Temperament and Character Inventory (TCI) scores. A total of 22 subjects free of psychiatric and somatic disorders were included in the matched high- and low-HA groups. The main outcome measure was regional 5-HTT binding potential (BPND) in high- and low-HA groups estimated with PET and [11C]N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ([11C]MADAM). In secondary analyses, 5-HTT BPND was correlated with other TCI dimensions. RESULTS: 5-HTT BPND did not differ between high- and low-HA groups in the midbrain or any other brain region. This result remained the same even after adjusting for other relevant TCI dimensions. Higher 5-HTT BPND in the raphe nucleus predicted higher scores in 'self-directedness'. CONCLUSIONS: This study does not support an association between the temperament dimension HA and serotonin transporter density in healthy subjects. However, we found a link between high serotonin transporter density and high 'self-directedness' (ability to adapt and control one's behaviour to fit situations in accord with chosen goals and values). We suggest that biological factors are more important in explaining variability in character than previously thought.

A prospective cohort study of deficient maternal nurturing attitudes predicting adulthood work stress independent of adulthood hostility and depressive symptoms.

Stressful childhood environments arising from deficient nurturing attitudes are hypothesized to contribute to later stress vulnerability. We examined whether deficient nurturing attitudes predict adulthood work stress. Participants were 443 women and 380 men from the prospective Cardiovascular Risk in Young Finns Study. Work stress was assessed as job strain and effort-reward imbalance in 2001 when the participants were from 24 to 39 years old. Deficient maternal nurturance (intolerance and low emotional warmth) was assessed based on mothers' reports when the participants were at the age of 3-18 years and again at the age of 6-21 years. Linear regressions showed that deficient emotional warmth in childhood predicted lower adulthood job control and higher job strain. These associations were not explained by age, gender, socioeconomic circumstances, maternal mental problems or participant hostility, and depressive symptoms. Deficient nurturing attitudes in childhood might affect sensitivity to work stress and selection into stressful work conditions in adulthood. More attention should be paid to pre-employment factors in work stress research.

Metabolic syndrome and short-term heart rate variability in young adults. The cardiovascular risk in young Finns study.

AIMS: Heart rate variability (HRV) can be used to estimate autonomic nervous control of the cardiovascular system. In middle-aged subjects, the metabolic syndrome (MetS) is associated with lower HRV. We hypothesized that alterations in autonomic balance are already present in young adults with the MetS, and analysed the association of short-term HRV with the MetS (using the National Cholesterol Education Program definition), in 1889 subjects aged 24-39 years. METHODS: Short-term (3 min) HRV analysis included high-frequency (HF), low-frequency (LF) and total (TP) spectral components of HRV and LF/HF ratio. RESULTS: The presence of the MetS was associated with lower HF, LF and TP in men and women, and with higher LF/HF ratio in women. In men, waist circumference was the strongest individual MetS component that associated with HRV. After adjustments for age and heart rate, MetS was associated with lower HF and higher LF/HF ratio in women, but only with a lower TP in men (all P < 0.05). CONCLUSIONS: MetS is associated with lower HRV in young adults. The individual components of MetS are differentially associated with HRV in men and in women. Our results are consistent with lower vagal activity and a possible increase in sympathetic predominance in women with the MetS. This sex difference in vagal activity and sympathovagal balance may partly explain the greater increase in cardiovascular risk associated with MetS in women than in men.

Work stress and new-onset migraine in a female employee population.

This prospective cohort study examined whether work stress, as indicated by the job strain model and the effort-reward imbalance model, predicts new-onset migraine among 19,469 female employees with no history of migraine at study entry. A baseline survey between 2000 and 2002 assessed work stress and demographic factors. Self-reported newly diagnosed migraine was measured at follow-up between 2004 and 2005 and 1281 new cases of migraine were detected. In logistic regression analysis adjusted for age, socioeconomic position and depression at baseline, no association between job strain and migraine was found. In contrast, high effort-reward imbalance was associated with slightly increased risk of migraine at follow-up, odds ratio 1.23 (95% confidence interval 1.04, 1.45). The proportion of new migraine cases attributable to high effort-reward imbalance was 6.2%. If the observed association is causal, our findings suggest that high effort-reward imbalance might function as a modifiable risk factor for new-onset migraine.

Sickness absence among female employees with migraine and co-existing conditions.

This prospective cohort study examined the risk of sickness absence among 27,127 female public-sector employees by status of migraine and co-existing conditions. A baseline survey was used to assess chronic disorders and demographic factors. Information on sickness absence in the 3 years following the survey was obtained from employers' registers. Migraine was related to 5.4 extra sickness absence days per person-year, with the corresponding figures being 14.6 and 6.1 for depression and respiratory disorders, respectively. After adjusting for age, marital status, socioeconomic status and presence of depression or respiratory disorders, employees with migraine had a 1.21 (95% confidence interval 1.18, 1.24) times higher risk of self-certified sickness absence episodes (< or = 3 days) than did those without migraine. The corresponding excess risk for medically certified absence episodes (> 3 days) was 1.15 (1.12, 1.19). Among employees with depression or respiratory disorders, secondary migraine was associated with an increased risk of sickness absence episode of 1.15 to 1.23. These findings suggest that migraine is associated with increased risk of recorded sickness absence independent of depression and respiratory disorders.

Is the association between job strain and carotid intima-media thickness attributable to pre-employment environmental and dispositional factors? The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: Most previous studies of job strain and cardiovascular risk have been limited to adult data. It remains unclear whether this association might be explained by factors already present before entering the labour market. This study examined whether pre-employment family factors and participants' own dispositional factors contribute to the relationship between job strain and carotid intima-media thickness (CIMT) among male employees. METHODS: The sample consisted of 494 men from the Cardiovascular Risk in Young Finns Study. Parental socioeconomic position and parental life dissatisfaction were assessed at 9-21 years of age and components of type A behaviour (Hunter-Wolf) were assessed at 12-24 years of age before the participants had entered the labour market. Job strain, education and CIMT were assessed at 27-39 years of age when all participants were employed. RESULTS: There was an association between higher job strain and increased CIMT in adulthood (mean 0.59 mm; 95% CI 0.42 to 0.76) which was only slightly affected on adjustment for parental socioeconomic position and parental life dissatisfaction as well as participants' education. However, the job strain/CIMT relationship attenuated by 17% to non-significant after taking into account the effect of the participants' type A behaviour components. CONCLUSIONS: In this contemporary cohort of men, lack of leadership (a type A behaviour component) contributed to the association between job strain and CIMT 15 years later, whereas pre-employment family factors had only a modest effect on this association.

Tryptophan hydroxylase 1 gene haplotypes modify the effect of a hostile childhood environment on adulthood harm avoidance.

We conducted a series of tests to determine whether there is any association between tryptophan hydroxylase 1 (TPH1) and temperament in adulthood. In addition to testing for main effects, we investigated whether TPH1 gene variation modifies the influence of childhood environment on temperament in adulthood. The subjects were 341 healthy adults whose childhood environment was assessed by their mothers in 1980 and who self-rated their temperaments twice, in 1997 and 2001. We found no association between the TPH1 gene and temperament; however, among women, the TPH1 gene modified a relationship between adverse childhood environment and harm avoidance in adulthood. This finding was confirmed in the same sample in another test setting 4 years later. The presence of the A/A haplotype of the TPH1 intron 7 A218A and A779C polymorphism predicted a high level of adulthood harm avoidance in the presence of a hostile childhood environment as defined in terms of emotional rejection, maternal neglect and harsh and inconsistent discipline. In addition, the findings suggest a gene-environment correlation for novelty seeking in men.

Cloninger's temperament dimensions and epidermal growth factor A61G polymorphism in Finnish adults.

This study examines a link between human temperament and epidermal growth factor (EGF). There is evidence that dopaminergic neurotransmission in the central nervous system has a role in temperament, especially in novelty seeking. Functional polymorphism in EGF gene has an impact on EGF production, and EGF, in turn, appears to affect the development of midbrain dopaminergic neurons. Epidermal growth factor gene A61G polymorphisms were studied in a randomly selected sample of 292 Finnish adults. Their temperaments were assessed twice (with a 4-year test-retest interval) with Cloninger's Temperament and Character Inventory consisting of four dimensions, i.e. novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (P). The findings on men showed a significant association between a presence of the G/G polymorphism and scoring in the highest tertile on NS in both test and retest. The same was true with men who scored high on RD, especially on sensitivity, in both tests. Among women, G/G polymorphism was associated with a stable high level of P. Importantly, temperament dimensions, as assessed with one test only, did not provide replicable associations with EGF polymorphism across the two measurements. Our results demonstrate the importance of reliable phenotype assessment and lend support to the hypothesis that dopaminergic activity is one factor underlying stable temperament.

Associations of temporal and energetic characteristics of behavior with depressive symptoms: A population-based longitudinal study within Strelau's Regulative Theory of Temperament.

BACKGROUND: Individual dispositions have previously been associated with increased risk for depressive symptoms. The direction of the association has been found to be sometimes reciprocal. We examined whether temperament traits are associated with depressive symptoms and whether depressive symptoms contribute to changes in temperament. METHODS: Participants (n=674-811) were from a population-based Young Finns Study. Temperament was assessed by a Finnish version of the Formal Characteristics of Behavior - Temperament Inventory. Depressive symptoms were assessed with modified BDI (mBDI) in 1997, 2001, 2007 and 2012, and BDI-II in 2012. RESULTS: Higher perseveration and emotional reactivity were associated with higher level of depressive symptoms, and higher endurance was associated with lower level of depressive symptoms in 2007 and 2012. These associations were independent of several potential confounders and baseline depressive symptoms. The results of cross-lagged structural equation modeling showed that the associations between temperament and depressive symptoms were reciprocal: briskness, endurance and activity decreased the risk for depressive symptoms while depressive symptoms decreased the level of these characteristics. Perseveration, emotional reactivity and depressive symptoms reinforced each other over time. LIMITATIONS: The depressive symptoms scales we used are not meant for measuring clinically diagnosed depression. The relationships between temperament traits and depressive symptoms were not strong enough to provide a clinical basis for guiding treatment. CONCLUSIONS: Lower perseveration, lower emotional reactivity and higher endurance seem to be health protective temperament characteristics that reduce the risk for depressive symptoms. The reciprocal associations between temperament and depressive symptoms imply mutual health protective and health declining effects. Clinical relevance of the study is that enhancing positive loops and self-concept, and supporting individual stress management might be helpful in prevention of depressive symptoms.

Feelings of exhaustion, emotional distress, and pituitary and adrenocortical hormones in borderline hypertension.

OBJECTIVE: To examine whether feelings of exhaustion and emotional distress reflecting chronic perceived stress contribute to a pattern of pituitary and adrenocortical responses that would in turn be able to distinguish borderline hypertensives from normotensive controls. DESIGN: A cross-sectional study. SETTING: Helsinki University Central Hospital. PARTICIPANTS: Twenty-one middle-aged, male borderline hypertensives (140/90 mmHg < or = blood pressure < 160/95 mmHg) and 69 healthy normotensive controls (blood pressure < 140/90 mmHg). Main outcome measures Basal pituitary-adrenocortical activity was assessed by measurements of plasma cortisol and adrenocorticotrophin concentrations during the oral glucose tolerance test. Cortisol responses to dexamethasone suppression and adrenocorticotrophin stimulation tests were measured to determine the functional pituitary-adrenocortical activity. Feelings of exhaustion, namely, feelings of excess fatigue, loss of energy, increased irritability, demoralization and emotional distress were measured using a questionnaire. RESULTS: As has previously been shown, feelings of exhaustion and emotional distress are associated with a hormonal pattern consisting primarily of an elevation in cortisol response to adrenocorticotrophin stimulation and secondarily of dominance of cortisol in the ratio of mean basal cortisol level to mean basal adrenocorticotrophin level. This particular neuroendocrine pattern, denoting a defeat type of reaction to stress, was in turn able to distinguish borderline hypertensives from normotensive controls significantly. Adjustment for age and health-related lifestyle factors including smoking, alcohol consumption and physical activity did not alter the difference found between the groups. CONCLUSIONS: The results suggest that the variance shared by feelings of exhaustion, emotional distress and pituitary-adrenocortical hormones could elucidate the mechanisms by which stress exerts its influence towards an increased risk for hypertension.

Type A behavior and metabolic syndrome precursors in young adults.

The association between type A behavior and a cluster of parameters of the metabolic syndrome was studied in 919 randomly selected healthy young adults. Type A behavior was measured using the Type A Behavior Questionnaire for the Finnish Multicenter Study and the Hunter Wolf A-B Rating Scale. The results showed that type A men scored higher on the "Metabolic Syndrome Precursors Factor," representing a metabolic entity, than did non-type A men. In addition, type A behavior had a moderating effect on the relationship between parameters of the metabolic syndrome, that is, interdependence of these somatic factors was stronger in type A men than in non-type A men. These findings were not true of women. It is discussed whether type A behavior might affect bodily functions through increased activity along the pituitary-adrenal system resulting in insulin resistance, compensatory hyperinsulinemia, and other characteristics of the metabolic syndrome.

Relationships between the pituitary-adrenal hormones, insulin, and glucose in middle-aged men: moderating influence of psychosocial stress.

We examined whether the relationships between the pituitary-adrenal hormones (corticotropin [ACTH) and cortisol), insulin, and glucose differ as a function of psychosocial stress defined in terms of vital exhaustion (VE) and depressive behavior (DB). The participants were 69 normotensive and 21 unmedicated borderline hypertensive (BH) middle-aged men whose work is stressful. Hormonal and metabolic variables were measured during an oral glucose tolerance test (OGTT), and the cortisol response to dexamethasone (DXM) suppression and intravenous ACTH stimulation was also measured. We found that the basal ACTH level during the OGTT was positively associated with the cortisol response to ACTH at 60 minutes, the fasting insulin level, and the insulin to glucose ratio among exhausted and high DB men, while the reverse was true for nonexhausted and low DB men. Also, a high cortisol response to ACTH, a low cortisol level during the OGTT, and a high ratio of these cortisol determinations (cortisol ratio) were associated with high fasting insulin and glucose levels, the summed insulin values, and the insulin to glucose ratio only among nonexhausted and low DB men; among exhausted and high DB men, these associations were less pronounced, absent, or in the opposite direction. The findings suggest that VE and DB have a moderating influence on the relationships among the hormonal and metabolic parameters studied. Psychosocial stress may affect the pituitary-adrenocortical system in complex ways, contributing thereby to insulin resistance, hyperinsulinemia, and coronary heart disease (CHD) risk.

Insulin resistance syndrome and autonomically mediated physiological responses to experimentally induced mental stress in adolescent boys.

We investigated the relationship between hemodynamic and other autonomically mediated responses to experimentally induced mental stress and the parameters of the insulin resistance syndrome (IRS) in 48 healthy adolescent boys. Mental stress was induced with mental arithmetic and the Stroop Color-Word Test. Heart rate (HR), finger blood volume (FBV), and skin conductance level (SCL) were recorded continuously during task performance. IRS parameters measured were serum insulin, high-density lipoprotein (HDL) cholesterol, serum triglyceride (TG), systolic blood pressure (SBP), subscapular skinfold (SSF), and subscapular to triceps skinfold ratio (STR). The results indicated that a high level and an increasing linear trend of HR and FBV during task performance were related, independently of each other and of body mass index (BMI), to a high insulin concentration. An increasing linear trend of HR during mental stress was also related to high SSFs independently of MI. In addition, a high SCL during task performance was associated with high TG levels, SSFs, and STRs. It is discussed whether stress-induced sympathetic overactivity might contribute to the development of the IRS.

Psychosocial stress and the insulin resistance syndrome.

We examined the association between psychosocial stress-related variables and insulin resistance syndrome (IRS) risk-factor clustering. In 90 middle-aged male volunteers, psychosocial stress-related variables, defined as feelings of excessive tiredness and as personality and behavioral factors reflecting a stress-inducing life-style (type A behavior, hostility, and anger), were significantly correlated with the hyperinsulinemia, hyperglycemia, dyslipidemia, hypertension, increased abdominal obesity, and increased plasminogen activator inhibitor-1 (PAI-1) antigen comprising the IRS. The correlations remained significant after adjusting for body mass index (BMI), age, educational level, smoking status, alcohol consumption, and physical activity. However, the different stress-related factors reflected different risk-factor clustering profiles. Type A behavior was associated with normotension and a normal metabolic profile (canonical r = .50, chi2(36) = 59.1, P = .008). Hostility was related to elevated systolic blood pressure (SBP) and elevated triglycerides (TGs) (canonical r = .38, chi2(14) = 23.2, P = .052), whereas feelings of excessive tiredness were related to abdominal obesity, augmented glycemic responses to glucose ingestion, dyslipidemia, and increased PAI-1 antigen (canonical r = .39, chi2(24) = 36.8, P = .046). Although hostility and feelings of excessive tiredness have partly overlapping but clearly different clinical and metabolic correlates, their combination represents a full-blown IRS. Thus, even though insulin resistance is presumably to some extent genetically determined, these results suggest that considering psychosocial stress may be beneficial in understanding IRS risk-factor clustering.