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Interethnic differences in the association of tumor necrosis factor promoter polymorphisms with systemic lupus
M Rudwaleit1, M Tikly, M Khamashta
1Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.
Objective:
To assess the role of polymorphisms in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene in susceptibility to systemic lupus erythematosus (SLE).
Methods:
Two ethnically different populations of patients with SLE (49 white from the UK and 49 black from South Africa) were genotyped for TNF-238 and TNF-308 polymorphisms using amplification refractory mutation system-polymerase chain reaction (PCR). HLA-DR genotypes were assigned to the patients and controls either serologically or by PCR and sequence specific oligonucleotides. The frequencies of the respective variants were compared between patients and ethnically matched controls.
Results:
No significant differences were found in the frequency of the TNF-238 variants in either ethnic group. At TNF-308, the TNF2 variant was significantly increased (p = 0.04) in white patients with SLE compared to controls. However, TNF2 was strongly associated with HLA-DR3 (p = 0.00002), which also showed a strong trend of increase in the white patients (p = 0.06). In contrast, in the black patients with SLE in whom DR2 but not DR3 was increased, the frequency of TNF2 was actually reduced rather than increased.
Conclusions:
The increase of TNF2 in Caucasians with SLE is most likely due to linkage disequilibrium between TNF2 and DR3. Furthermore, the observation that TNF2 seems to be reduced in blacks with SLE strongly suggests this polymorphism is not an independent risk factor for SLE. Overall, our data indicate that the TNF-238 and TNF-308 promoter polymorphisms do not confer susceptibility to SLE.