Plasma Tumor Necrosis Factor α Levels and the –238* A Promoter Polymorphism in Patients with Antiphospholipid Syndrome

Abstract

Summary Objectives. To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFα in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNF and disease. Patients and Method. We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFα levels were determined in plasma from 35 patients’ and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. Results. TNFα 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 [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy 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 haplotype 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 TNFα levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFα may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNFα genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.

Increased level of tumor necrosis factor-α in patients with antiphospholipid syndrome: marker not only of inflammation but also of the prothrombotic state

“…Our results corroborate with those of Bertolaccini et al [25], who showed elevated TNF-a levels in patients with APS. Also, in accordance with our findings, they were unable to show any differences between its primary and secondary form (Table 1).…”

Associations between tumor necrosis factor-α and lymphotoxin-α polymorphisms and idiopathic recurrent miscarriage

“…Our results were reminiscent of a previous study, in which the TNF-a K238G/A, but not the K308G/A, SNP were associated with RM (Bertolaccini et al 2001). This lack of association of the TNF-a K308G/A SNP with increased RM risk was also reported for Caucasian A recent meta-analysis (Daher et al 2003) confirmed the lack of association of the TNF-a K308G/A SNP with RM, and suggested instead that interferon-g (874T/T) and IL-10 (K1082G/G) gene variants represented stronger RM inherited risk factors.…”

Tumor necrosis factor α and lymphotoxin α haplotypes in idiopathic recurrent pregnancy loss

“…The present results were reminiscent of an earlier study, in which the TNFa À238G/A, but not the À308G/A, SNP was associated with RM (28). This lack of association of the TNFa À308G/A SNP with increased RM risk was also reported for Caucasian (17,23,28,29) and Iranian (30) women, and in apparent partial disagreement with the study of Costeas et al (21).…”