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

Background:

It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease.

Methods:

We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985–2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2–4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death).

Results:

There were 1086 incident events in 743 948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18–2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06–1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000).

Interpretation:

The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain.Psychosocial work stress, denoted by job strain, is associated with an elevated risk of coronary artery disease.^1–7 This association is apparent across strata of sex, age, socioeconomic status and region, and it does not appear to be completely explained by confounding.⁷ For many people, avoidance of stress at work is unrealistic. The absence of strong evidence for effective interventions to reduce job strain therefore raises the challenge of identifying additional approaches for dealing with the health impact of stress in the workplace.Guidelines for the prevention of heart disease emphasize the importance of a healthy lifestyle — physical activity, a healthy diet (and healthy weight) and not smoking — in lowering disease risk.^8–11 Whether a healthy lifestyle offsets the deleterious impact of job strain on coronary artery disease remains unclear. A straightforward approach to test this hypothesis would involve comparing the rates of coronary artery disease among people with job strain and an unhealthy lifestyle with the rates among those with job strain and a healthy lifestyle. If a marked difference is apparent, one would consider a healthy lifestyle to be the likely factor contributing to the reduced risk among those with job strain. However, such stratifications require a large, well-characterized dataset, which to date has been lacking. We pooled individual-level data for more than 100 000 men and women participating in 7 cohort studies to examine the combined associations of job strain and lifestyle with risk of coronary artery disease.     

Treatment of data on the size of individual insects from field samples

In sampling a population of insects for an estimate of their average size it is common practice to collect, trap, etc. groups of individuals from a number of points; the individual size measurements are then lumped together and treated as a random sample of the population. This lumping procedure is usually wrong since it can give too low a figure for the standard error of the mean. The low figure is due to the presence of heterogeneity of variation in size among the individuals of the population; neighbours tend to vary less than individuals far apart.Examples of heterogeneity (in samples from populations of garden chafers, 17-year cicadas and crane-fly larvae) are described and discussed. In the case of the crane fly larvae the scale of the heterogeneity could be assessed. Heterogeneity sometimes appears in groups of larvae no more than 1 metre apart.The correct method of calculating the standard error of the mean is described but it is shown that an alternative approximate method gives virtually the same result. Two sampling methods designed to estimate size specifically are discussed.

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Behandlung von groenmassen einzelnen insekten aus feldfängen

Zusammenfassung Bei der Probeetnahme einer Population von Insekten zur Bestimmung ihrer durchschnittlichen Körpergröße ist es allgemein üblich, Individuengruppen von einer Anzahl von Punkten zu sammeln, zu fangen usw. Die individuellen Größenmaße werden dann zusammengefaßt und als Zufallsstichprobe der Population behandelt. Diese Vereinigungsprozedur ist gewöhnlich fehlerhaft, weil sie einen zu niedrigen Wert für die Standartabweichung des Mittelwertes ergeben kann. Dieser niedrige Wert beruht auf der Wirkung der heterogenen Variabilität der Größe unter den Angehörigen der Population. Benachbarte Tiere variieren meist weniger als weit voneinander entfernt lebende.Beispiele von Heterogenität (in Stichproben aus Populationen von Junikäfern, 17jährigen Zikaden und Schnakenlarven) werden beschrieben und diskutiert. Im Falle der Schnakenlarven konnte die Skala der Heterogenität bestimmt werden. Heterogenität tritt manchmal in Gruppen von Larven auf, die nicht mehr als 1 m voneinander entfernt lebten.Die korrekte Methode zur Berechnung der Standartabweichung vom Mittel wird beschrieben, aber es wird gezeigt, daß eine alternative Nährungsmethode praktisch das gleiche Resultat ergibt. Zwei Probenahme-Methoden, die besonders zur Größenbestimmung geeignet sind, werden besprochen.

     

Merging microarray data from separate breast cancer studies provides a robust prognostic test

Background  

There is an urgent need for new prognostic markers of breast cancer metastases to ensure that newly diagnosed patients receive appropriate therapy. Recent studies have demonstrated the potential value of gene expression signatures in assessing the risk of developing distant metastases. However, due to the small sample sizes of individual studies, the overlap among signatures is almost zero and their predictive power is often limited. Integrating microarray data from multiple studies in order to increase sample size is therefore a promising approach to the development of more robust prognostic tests.     

Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies

Background

The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule.

Methods and Findings

We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%–90.9%) and specificity was 49.6% (95% CI 29.2%–70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%–96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%–94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%–98.0%) and 90.0% (95% CI 88.6%–91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%).

Conclusions

Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT. Please see later in the article for the Editors'' Summary     

Androgens and breast cancer risk

Transdermal testosterone supplementation is a treatment option for postmenopausal women with distressful decreased libido. Side effects are minor, but there is a long-term safety concern with respect to breast cancer, as women with high testosterone serum levels appear to be at a significantly increased risk to have or to develop breast cancer within a few years. Epidemiological studies of sufficient duration to study long-term effects of testosterone supplementation are limited, both in number and in methodological quality and are, therefore, inconclusive. Preclinical studies do not provide evidence for an androgen receptor-mediated stimulating effect of androgens on breast epithelium. However, one biologically plausible possibility, which cannot be ruled out, is that exogenous androgens become mitogenic after aromatization into bioactive oestradiol, either in peripheral fat or within the breast or even within small occult tumours. The evidence available so far makes counselling women interested in testosterone supplementation for distressful low sexual desire, more of an art than science.     

Effect of breast self-examination techniques on the risk of death from breast cancer

OBJECTIVE: To measure the effect of breast self-examination (BSE) technique and frequency on the risk of death from breast cancer. DESIGN: Case-control study nested within the Canadian National Breast Screening Study (NBSS). SETTING: The Canadian NBSS, a multicentre randomized controlled trial of screening for breast cancer in Canadian women. SUBJECTS: The case subjects were 163 women who had died from breast cancer and 57 women with distant metastases. Ten control subjects matched by 5-year age group, screening centre, year of enrolment and random allocation group were randomly selected for each case subject. EXPOSURE MEASURES: Self-reported BSE frequency before enrolment in the NBSS, annual self-reports of BSE frequency during the program and annual objective assessments of BSE technique. OUTCOME MEASURES: Odds ratios (ORs) associated with BSE practice were estimated by conditional multiple logistic regression modelling, which permitted control of covariates. RESULTS: Relative to women who, when assessed 2 years before diagnosis, examined their breasts visually, used their finger pads for palpation and examined with their 3 middle fingers, the OR for death from breast cancer or distant metastatic disease for women who omitted 1, 2 or 3 of these components was 2.20 (95% confidence interval [CI] 1.30 to 3.71, p = 0.003). The OR for women who omitted 1 of the 3 components was 1.82 (95% CI 1.00 to 3.29, p = 0.05), for those who omitted 2 of the 3 components, 2.84 (95% CI 1.44 to 5.59, p = 0.003), and for those who omitted all 3 components, 2.95 (95% CI 1.19 to 7.30, p = 0.02). The results remained unchanged after adjustment for potential confounders. CONCLUSION: The results, obtained with the use of prospectively collected data, suggest that the performance of specific BSE components may reduce the risk of death from breast cancer.     

Birth weight, breast cancer and the potential mediating hormonal environment

Background

Previous studies have shown that woman’s risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother’s own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer.

Methods and Findings

Risk of breast cancer in relation to a first infant’s birth weight, mother’s own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha-fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years) 31 women (7.6 %) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2–5.2; P = 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2–5.6; P = 0.021). An infant’s birth weight had a strong positive relationship with the mother’s serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships.

Conclusions

Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother’s own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression.     

Contribution of individual PKC isoforms to breast cancer progression

The protein kinase C (PKC) family of serine/threonine kinases has been intensively studied in cancer since their discovery as major receptors for the tumor-promoting phorbol esters. The contribution of each individual PKC isozyme to malignant transformation is only partially understood, but it is clear that each PKC plays different role in cancer progression. PKC deregulation is a common phenomenon observed in breast cancer, and PKC expression and localization are usually dynamically regulated during mammary gland differentiation and involution. In fact, the overexpression of several PKCs has been reported in malignant human breast tissue and breast cancer cell lines. In this review, we summarize the knowledge available on the specific roles of PKC isoforms in the development, progression, and metastatic dissemination of mammary cancer. We also discuss the role of PKC isoforms as therapeutic targets, and their potential as markers for prognosis or treatment response.     

Steroid biochemistry and categorization of breast cyst fluid: relation to breast cancer risk

Patients bearing macrocysts of the breast are at higher risk of later developing cancer. The fluid filling the cysts (breast cysts fluid, BCF) contains unusual amounts of steroid conjugates, first androgen and estrogen sulfates. Measuring BCF cations (K⁺, Na⁺) allows categorization of cysts into two major subsets (type I and type II) that are associated with a different degree and/or turnover of apocrine metaplastic cells in the lining epithelium. Type I cysts (high K⁺/ Na⁺ ratio) accumulate huge amounts of dehydroepiandrosterone sulfate, estrone sulfate, androstane-3, 17β-diol glucuronide, androsterone glucuronide and contain more testosterone and dihydrotestosterone than type II. Conversely, type II cysts (low K⁺/Na⁺ ratio) contain more progesterone and pregnenolone. A cohort study was started in 1983 at the Cancer Prevention Center, Ravenna, Italy, with the aim of evaluating the relationships between the biochemistry of BCF and the incidence of breast cancer in women with gross cystic disease (GCD) of the breast. The bimodal distribution of the cationic pattern has been confirmed from data obtained in 798 patients aspirated. The risk of cyst relapse was significantly higher among women with type I cysts or with multiple cysts at presentation. Twelve incident cases of breast cancer have been diagnosed among women whose BCF was categorized. Eleven out of 12 cases had type I or multiple cysts. The cumulative incidence of breast cancer among patients bearing type I cysts was 2.5%. We conclude that women with GCD bearing type I cysts have an increased breast cancer risk when compared with the counterpart bearing type II cysts or the general population.     

Estrogen, alcohol and breast cancer risk

Estrogen replacement has been used for many years to reverse the hypoestrogenic symptoms of menopause and prevent osteoporosis. Studies have found that estrogen replacement also decreases cardiovascular risk. In addition, social use of alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen replacement therapy and alcohol use have been proposed to have cardiovascular benefits, and are often used in combination. Epidemiologic evidence indicates that estrogen replacement therapy after menopause increases breast cancer risk. Regular alcohol consumption is also associated with increase in risk. However, interactions between the two are poorly understood. In addition, if alcohol alters circulating estrogen levels in estrogen users, this may have implications in terms of altering the risks:benefit ratio of estrogen replacement in an undesirable direction. For example, there are data suggesting that the use of both alcohol and estrogen may increase breast cancer risk more than the use of either one alone. Data support both acute and chronic effects of alcohol in raising circulating estrogen levels in premenopausal women on no hormonal medications. In postmenopausal women studies focusing on acute effects of alcohol on estrogen metabolism indicate that alcohol has a much more pronounced effect in women using estrogen replacement than in those who do not. Studies evaluating chronic effects of alcohol ingestion on circulating estrogens in postmenopausal women are needed.     

Risk factors and risk reduction of breast cancer

Because of its increasing incidence, breast cancer is a significant burden for women worldwide. In industrialized countries, breast cancer is the second-leading cause of cancer-related deaths among women, and it is estimated that 1 in every 8 women will develop the disease during her lifetime. Sufficient evidence indicates that a number of genetic, environmental and lifestyle risk exposures during life may play important roles in the etiology of this disease. The purpose of this paper is to review some etiologic factors and underlying mechanisms in relation to breast cancer risk. Based on the published literature, there is sufficient evidence that some established factors are associated with breast cancer risk. Age, early age at menarche, late menopause, height, post-menopausal obesity, family history of breast cancer, ionizing radiation, oral contraceptives, hormonal replacement therapy, mammographic density, some gene mutations and clinical conditions, such as benign breast disease, are associated with an increased risk of breast cancer. The risk decreases with early childbearing, high parity and physical activity, and breastfeeding. Alcohol increases the risk, while caloric restriction may confer protection from breast cancer. Epidemiological evidence for other nutritional factors is insufficient. These results suggest that breast cancer is a multifactorial disease where genetic susceptibility, environment, nutrition and other lifestyle risk factors interact. Better identification of modifiable risk factors and risk reduction of breast cancer may allow implementation of useful strategies for prevention.     

HIV tropism and decreased risk of breast cancer

Background

During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.

Methods and Findings

We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load ≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002–0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001–0.83). Adjustment for CD4⁺ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.

Conclusions

Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk.     

A metadata approach for clinical data management in translational genomics studies in breast cancer

Background

Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10–50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family.

Methods

We have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15).

Results

We found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15).

Conclusion

The similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.     

Epstein-Barr virus infection and sporadic breast cancer risk: a meta-analysis

Background

A large number of epidemiological studies have evaluated the association between Epstein-Barr virus infection and breast carcinoma risk but results have been inconsistent.

Methodology

Research using the polymerase chain reaction technique for detecting the Epstein-Barr virus was selected; 24 studies and 1535 cases were reviewed. Information on the study populations, sample types, publication calendar period and histological types of breast carcinoma were collected. An unconditional logistic regression model was used to analyze potential parameters related to the Epstein-Barr virus prevalence. A Kappa test was used to evaluate the consistency in detecting different Epstein-Barr virus DNA regions. Nine studies that included control groups and 1045 breast cancer cases were adopted in this meta-analysis.

Conclusions

We found that 29.32% of the patients with breast carcinoma were infected with the Epstein-Barr virus. The prevalence of Epstein-Barr was highest in Asia (35.25%) and lowest in the USA (18.27%). Statistical analysis revealed a trend that showed lobular breast carcinoma might have the strongest association with Epstein-Barr virus infection. This meta-analysis showed a significant increase in breast malignancy risk in patients testing positive for the Epstein-Barr virus (OR = 6.29, 95% CI = 2.13–18.59). This result suggests that an Epstein-Barr virus infection is statistically associated with increased breast carcinoma risk.