Plasma tumor necrosis factor alpha levels and the-238*A promoter polymorphism in patients with antiphospholipid syndrome

Objectives. To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNF alpha in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HL A class II genotypes with both plasma TNF alpha and disease. Patients and M ethod. We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFa levels were determined in plasma from 35 patients' and 21 co ntrols using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -2 38 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 an d DRB1 genotypes were determined by PCR using sequence specific primers. Re sults. TNF alpha levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.5 1-1.6]. respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did n ot differ between patients and controls. In contrast, TNFA-238*A positive g enotype was more frequent in APS patients with arterial thrombosis and preg nancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3. 95 [95% CI 1.3-11.7], p = 0.01: respectively). DQB1*0303-DRB1*0701 haplotyp e was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6- 959], p<0.0001) as well as in APS patient's group (OR 54.2 [95% CI 9.6-306. 5]. p<0.0001). Conclusions. Raised plasma TNFa levels were found in patient s with APS. As a prothrombotic and proinflammatory cytokine, TNFa may be in volved in the development of clinical features of APS. The lack of correlat ion between the TNFA-238 polymorphism and plasma levels associated with dis ease suggests that the TNF genetic marker may only indirectly relate to pro tein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.