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).