Elevated Plasma C-reactive protein in chronically distressed subjects who carry the A allele of the TNF-alpha -308 G/A polymorphism.

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)-alpha 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-alpha 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-alpha 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-alpha -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.