Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients

<p>Abstract</p> <p>Background</p> <p>Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of coronary artery disease (CAD). A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility.</p> <p>Results</p> <p>Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case:control cohort yielded 2,438 genes with significant CAD association (p < 0.05), and identified the clinical/demographic factors with the largest effects on gene expression as age, sex, and diabetic status. RT-PCR analysis of 88 CAD classifier genes confirmed that diabetic status was the largest clinical factor affecting CAD associated gene expression changes. A second microarray cohort analysis limited to non-diabetics from the multi-center PREDICT study (198 patients; 99 case: control pairs matched for age and sex) evaluated gene expression, clinical, and cell population predictors of CAD and yielded 5,935 CAD genes (p < 0.05) with an intersection of 655 genes with the CATHGEN results. Biological pathway (gene ontology and literature) and statistical analyses (hierarchical clustering and logistic regression) were used in combination to select 113 genes for RT-PCR analysis including CAD classifiers, cell-type specific markers, and normalization genes.</p> <p>RT-PCR analysis of these 113 genes in a PREDICT cohort of 640 non-diabetic subject samples was used for algorithm development. Gene expression correlations identified clusters of CAD classifier genes which were reduced to meta-genes using LASSO. The final classifier for assessment of obstructive CAD was derived by Ridge Regression and contained sex-specific age functions and 6 meta-gene terms, comprising 23 genes. This algorithm showed a cross-validated estimated AUC = 0.77 (95% CI 0.73-0.81) in ROC analysis.</p> <p>Conclusions</p> <p>We have developed a whole blood classifier based on gene expression, age and sex for the assessment of obstructive CAD in non-diabetic patients from a combination of microarray and RT-PCR data derived from studies of patients clinically indicated for invasive angiography.</p> <p>Clinical trial registration information</p> <p>PREDICT, Personalized Risk Evaluation and Diagnosis in the Coronary Tree, <url>http://www.clinicaltrials.gov</url>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00500617">NCT00500617</a></p

Gene Expression Patterns in Peripheral Blood Correlate with the Extent of Coronary Artery Disease

Systemic and local inflammation plays a prominent role in the pathogenesis of atherosclerotic coronary artery disease, but the relationship of whole blood gene expression changes with coronary disease remains unclear. We have investigated whether gene expression patterns in peripheral blood correlate with the severity of coronary disease and whether these patterns correlate with the extent of atherosclerosis in the vascular wall

Cardiovascular disease and the role of oral bacteria

In terms of the pathogenesis of cardiovascular disease (CVD) the focus has traditionally been on dyslipidemia. Over the decades our understanding of the pathogenesis of CVD has increased, and infections, including those caused by oral bacteria, are more likely involved in CVD progression than previously thought. While many studies have now shown an association between periodontal disease and CVD, the mechanisms underpinning this relationship remain unclear. This review gives a brief overview of the host-bacterial interactions in periodontal disease and virulence factors of oral bacteria before discussing the proposed mechanisms by which oral bacterial may facilitate the progression of CVD

Measuring the attractiveness of rural communities in accounting for differences of rural primary care workforce supply

Introduction: Many rural communities continue to experience an undersupply of primary care doctor services. While key professional factors relating to difficulties of recruitment and retention of rural primary care doctors are widely identified, less attention has been given to the role of community and place aspects on supply. Place-related attributes contribute to a community's overall amenity or attractiveness, which arguably influence both rural recruitment and retention relocation decisions of doctors. This bi-national study of Australia and the USA, two developed nations with similar geographic and rural access profiles, investigates the extent to which variations in community amenity indicators are associated with spatial variations in the supply of rural primary care doctors. Methods: Measures from two dimensions of community amenity: geographic location, specifically isolation/proximity; and economics and sociodemographics were included in this study, along with a proxy measure (jurisdiction) of a third dimension, environmental amenity. Data were chiefly collated from the American Community Survey and the Australian Census of Population and Housing, with additional calculated proximity measures. Rural primary care supply was measured using provider-to-population ratios in 1949 US rural counties and in 370 Australian rural local government areas. Additionally, the more sophisticated two-step floating catchment area method was used to measure Australian rural primary care supply in 1116 rural towns, with population sizes ranging from 500 to 50 000. Associations between supply and community amenity indicators were examined using Pearson's correlation coefficients and ordinary least squares multiple linear regression models. Results: It was found that increased population size, having a hospital in the county, increased house prices and affluence, and a more educated and older population were all significantly associated with increased workforce supply across rural areas of both countries. While remote areas were strongly linked with poorer supply in Australia, geographical remoteness was not significant after accounting for other indicators of amenity such as the positive association between workforce supply and coastal location. Workforce supply in the USA was negatively associated with fringe rural area locations adjacent to larger metropolitan areas and characterised by long work commutes. The US model captured 49% of the variation of workforce supply between rural counties, while the Australian models captured 35-39% of rural supply variation. Conclusions: These data support the idea that the rural medical workforce is maldistributed with a skew towards locating in more affluent and educated areas, and against locating in smaller, poorer and more isolated rural towns, which struggle to attract an adequate supply of primary care services. This evidence is important in understanding the role of place characteristics and rural population dynamics in the recruitment and retention of rural doctors. Future primary care workforce policies need to place a greater focus on rural communities that, for a variety of reasons, may be less attractive to doctors looking to begin or remain working there

Epigenetic changes caused by diabetes and their potential role in the development of periodontitis

Aims/Introduction Periodontal disease, a chronic inflammation induced by bacteria, is closely linked with diabetes mellitus. Many complications associated with diabetes are related to epigenetic changes. However, the exact epigenetic changes whereby diabetes affects periodontal disease remain largely unknown. Thus, we sought to investigate the role of diabetes-dependent epigenetic changes of gingival tissue in the susceptibility to periodontal disease. Materials and Methods We studied the effect of streptozotocin-induced diabetes in minipigs on gingival morphological and epigenetic tissue changes. Accordingly, we randomly divided six minipigs into two groups: streptozotocin-induced diabetes group, n = 3; and non-diabetes healthy control group, n = 3. After 85 days, all animals were killed, and gingival tissue was collected for histology, deoxyribonucleic acid methylation analysis and immunohistochemistry. Results A diabetes mellitus model was successfully created, as evidenced by significantly increased blood glucose levels, reduction of pancreatic insulin-producing β-cells and histopathological changes in the kidneys. The gingival tissues in the diabetes group presented acanthosis of both gingival squamous epithelium and sulcular/junctional epithelium, and a significant reduction in the number and length of rete pegs. Deoxyribonucleic acid methylation analysis showed a total of 1,163 affected genes, of which 599 and 564 were significantly hypermethylated and hypomethylated, respectively. Immunohistochemistry staining showed that the hypomethylated genes – tumor necrosis factor-α and interleukin-6 – were positively expressed under the junctional epithelium area in the diabetes group. Conclusions Diabetes mellitus induces morphological and epigenetic changes in periodontal tissue, which might contribute to the increased susceptibility of periodontal diseases in patients with diabetes.</p

Hostile attribution bias and negative reciprocity beliefs exacerbate incivility's effects on interpersonal deviance

The purpose of this study was to examine the moderating roles of hostile attribution bias and negative reciprocity beliefs in the relationship between workplace incivility, as perceived by employees, and their interpersonal deviance. Data were collected using a three-wave survey research design. Participants included 233 employees from a large manufacturing company in China. Hierarchical regression analyses were used to test the hypothesized relationships. Our study revealed that hostile attribution bias and negative reciprocity beliefs strengthened the positive relationship between workplace incivility and interpersonal deviance. This relationship was the most positive when both hostile attribution bias and negative reciprocity beliefs were high. The findings provided evidence that directing employees to depress hostile attribution bias and negative reciprocity beliefs may attenuate the effects of workplace incivility on interpersonal deviance. Implications for theory, research, and management practice are discussed