Genetic impact of TNF-beta on risk factors for coronary atherosclerosis.

BACKGROUND: Inflammatory processes are considered to play an important role in the development of coronary atherosclerosis. The proinflammatory cytokine, tumor necrosis factor beta (TNF-beta), is thought to contribute to the pathogenesis of atherosclerosis. STUDY DESIGN: In this clinical study, the influence of genetic variants of TNF-beta (c.7G>A, IVS1+90G>A, C13R, T60N) on major coronary risk factors, including gender, smoking, history of cardiovascular diseases, biochemical data (inflammatory markers, factors of lipid metabolism, coagulation/fibrinolysis balance), and angiographically-proven coronary state, was investigated in 176 European Caucasian probands (130 males, mean age: 51.9 +/- 8.9 y). RESULTS: The most frequent combinations of the polymorphisms investigated were significantly associated with four of the coronary risk factors evaluated: hypertension, body mass index, the common inflammatory marker TNF-alpha (mRNA expression), and fibrinogen (p < 0.05). However, on testing the impact of the genetic background on the incidence of coronary stenosis in this sample of European Caucasians, no significant influence of these polymorphisms (stepwise binary logistic regression analysis) could be proven. These findings emphasise a distinct influence of TNF-beta polymorphisms on important modulators of the development of coronary atherosclerosis, but exclude its genetic background, investigated in this study as an independent coronary risk factor.

Relation between the tumor necrosis factor-alpha (TNF-alpha) gene and protein expression, and clinical, biochemical, and genetic markers: age, body mass index and uric acid are independent predictors for an elevated TNF-alpha plasma level in a complex risk model.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of numerous complex diseases. The plasma level of this pro-inflammatory cytokine is associated with a variety of different risk factors, but little is known about the genetic background and the complex interactions. METHODS: in this clinical study, correlations were studied between plasma levels of circulating TNF-alpha protein (ELISA), its mRNA expression in monocytes (RT-PCR) and genetic variants of TNF-alpha gene (SSCP), with several diseases, including obesity, atherosclerosis, diabetes mellitus, hypertension, as well as risk factors such as age, gender, inflammatory markers, the coagulation\fibrinolysis balance, and lipid metabolism. One hundred and ninety four clinically and biochemically well-characterized patients were enrolled. RESULTS: At the transcriptional level, measured in monocytes, no association with any clinical or biochemical parameter investigated was found, including TNF-alpha protein level. Investigating the influence of genetic variants of the TNF-alpha gene on mRNA and protein levels, only one promoter polymorphism, namely c.-238G > A, was shown to be associated with transcriptional but not with translational expression. However, at the translational level, significant positive, but weak associations were determined for obesity (P -/+ 0.037), age (P -/+ 0.038), uric acid (P < 0.001), body mass index (P -/+ 0.01), plasminogen (P -/+ 0.013), and fibrinogen (P -/+ 0.002) in bivariate regression analyses, whereas HDL-cholesterol (P -/+ 0.005) was shown to be negatively correlated. However, investigating confounding effects in stepwise multivariate regression analysis, body mass index (P -/+ 0.009), uric acid (P -/+ 0.026) and age (P -/+ 0.037) turned out to be significantly associated with plasma levels of circulating TNF-alpha (adjusted R(2) -/+ 0.117; SE: 0.688).

Role of LDL receptor-related protein (LRP) in coronary atherosclerosis.

The development and progression of coronary atherosclerosis is influenced by a variety of genetic and environmental factors. Among the genetic factors, the cell surface receptor LRP/A2MR (LDL receptor-related protein/alpha2-macroglobulin receptor) was shown to be involved in a variety of biological processes leading to atherosclerotic plaque formation. That is why the individual expression of this receptor may, therefore, be considered as an evident predictor for coronary atherosclerosis. In this clinical ex vivo study the expression was measured by competitive RT-PCR and macroarray analysis in native monocytes. Both methods were first tested in an in vitro model using different human cells and cell lines (fibroblasts: chorion, skin; endothelial cells from umbilical cord vein; monocyte cell line: Mono-Mac-6): after stimulation with an LRP/A2MR ligand, leptin, the anticipated direct effect of this ligand, namely an increase in both receptor mRNA and protein expression, was confirmed. In disease-related ex vivo studies the mRNA and protein-expression of LRP/A2MR was investigated in 36 male patients suffering from myocardial infarction. In comparison to the control group (36 healthy male blood donors), a significant up-regulation of mRNA was detected in the myocardial infarction patient group (control: 122.3 ag/cell versus patients: 223 ag/cell; P<0.001). Investigating the LRP/A2MR protein expression a significant down-regulation of protein expression was determined in the patient group (control: 6 pg/cell versus patients: 1.6 pg/cell; P<0.001). The ratio of LRP/A2MR mRNA and protein expression is obviously an evident marker for coronary atherosclerosis, recommendable for the assessment of the individual coronary risk profile.