Gene polymorphism at position-308 of the tumor necrosis factor alpha promotor is not associated with disease progression in multiple sclerosis patients

Tumor necrosis factor-alpha (TNF alpha) is a pluripotent proinflammatory cy tokine and is thought to play an important role in the inflammatory process of multiple sclerosis (MS). A G-->A transition in the TNF alpha promotor a t position -308 (TNF2 allele) has been shown to be associated with increase d TNF alpha production. This study was designed to detect wether the TNF2 a llele is associated with disease progression in MS. We examined the TNF alp ha -308 polymorphism with an allelic discrimination PCR to detect the G-->A transition in the genomic DNA of 283 MS patients from Germany and in 72 pa tients with amyotrophic lateral sclerosis (ALS) and 66 with stroke from the same genetic background who served as controls. Disease severity was defin ed by the progression index (PI) and by progression to the important clinic al landmarks of Extended Disability Status Score (EDSS) 3.5 and 6. In addit ion, we evaluated the TNF alpha mRNA expression in whole blood with quantit ative PCR. No differences were found between the presence of the TNF2 allel e in MS, ALS, or stroke patients. Among the MS patients the TNF2 allele was not associated with a certain disease course. No association was found bet ween the accumulation of neurological deficits and progression to clinical landmarks. Although MS patients with the TNF2 allele tended to progress mor e rapidly from EDSS 3.5 to EDSS 6 this difference was nonsignificant (P = 0 .2). Nevertheless, we observed significantly higher TNF alpha mRNA expressi on in blood cells of stable patients carrying the TNF2-allele in comparison to the group with the wild type (P = 0.024). To examine the effect of gene tic background we examined the DNA of 60 MS patients and 20 healthy control s in a Cypriot population of Greek origin. There was a significantly lower frequency of the TNF2 allele in the Cyprus population than in Germans (P = 0.01). No significant differences were found between the frequencies of the TNF2 allele in Cypriot MS patients and controls. Although the TNF2 allele is associated with higher TNF alpha mRNA baseline levels, our data indicate that this allele appears not to contribute to MS susceptibility or severit y. In addition our data demonstrate that the TNF alpha -308 polymorphism is segregated differentially in two European populations of different genetic origin.