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Elevated Plasma C-Reactive Protein in Chronically Distressed Subjects Who Carry the A Allele of the TNF- -308 G/A Polymorphism

From the Institute for Behavioral Sciences, Swiss Federal Institute of Technology, Zürich, Switzerland (P.J., R.v.K., J.E.F.); Department of General Internal Medicine, University Hospital, Bern, Switzerland (R.v.K.) and the Institute of Clinical Chemistry, University Hospital Zürich, Switzerland (F.E.M.).

Address correspondence and reprint requests to Joachim E. Fischer, M.D., M.Sc., Swiss Federal Institute of Technology, Institute for Behavioral Sciences, Turnerstrasse 1, CH-8092 Zürich / Switzerland. E-mail: fischer{at}ifv.gess.etzh.ch

OBJECTIVE: Sustained psychological stress may result in a state operationalized as "vital exhaustion." Exhaustion predicted coronary artery disease (CAD) events whereby increased inflammatory activity might mediate this link. Moreover, there is an emerging importance of gene–environmental interactions in CAD. We investigated the effect of exhaustion severity on plasma levels of C-reactive protein (CRP) and whether exhaustion might regulate CRP levels via the –308G/A polymorphism of the tumor necrosis factor (TNF)- gene.

METHODS: We assessed exhaustion in 275 industrial employees (mean age ± SD, 41 ± 9 years, 88% men) using the Maastricht Questionnaire. Subjects were stratified as per exhaustion severity: none (N = 80), moderate (N = 128), and severe (N = 67). The TNF- polymorphism was determined by real-time polymerase chain reaction, and plasma CRP levels were measured by a high-sensitivity immunoassay.

RESULTS: There was a significant interaction between exhaustion and the TNF- polymorphism, explaining 4.5% in the variance of plasma CRP values (F(5,271) = 2.47, p = .033); the result held after controlling for classic cardiovascular risk factors. Adjusted mean CRP levels across exhaustion strata in GA (N = 70) and AA (N = 3) carriers combined were 0.91 mg/l (none), 1.78 mg/l (moderate), and 2.61 mg/l (severe) as compared with 1.24 mg/l, 1.61 mg/l, and 1.36 mg/l for the GG wild-type (N = 202).

CONCLUSION: The findings suggest that the A allele of the TNF- -308 G/A polymorphism may mediate inflammation with exhaustion in a dose-response relationship, while with the GG wild-type exhaustion severity seems unrelated to CRP levels. The finding provides a rationale for gene-environmental interactions by which psychosocial factors may promote atherosclerosis and CAD.

Key Words: exhaustion, • C-reactive protein, • tumor necrosis factor, • polymorphism, • cardiovascular disease.

Abbreviations: BP = blood pressure;; CAD = coronary artery disease;; CRP = C-reactive protein;; ELISA = enzyme-linked immunosorbent assay;; HbA1c = glycosylated hemoglobin A1c;; HDL = high-density lipoprotein cholesterol;; LDL = low-density lipoprotein cholesterol;; PTCA = percutaneous transluminal coronary angioplasty;; TNF- = tumor necrosis factor alpha.

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