Gene polymorphism at position −308 of the tumor-necrosis -factor-α (TNF-α) in Multiple Sclerosis and it's influence on the regulation of TNF-α production

Abstract

Tumor-necrosis-factor-α (TNF-α) is a major mediator of the inflammatory immune response and may play an important role in the pathogenesis and progression of Multiple Sclerosis (MS). Increased TNF-α levels of cerebrospinal fluid (CSF) and peripheral blood were found in patients with chronic progressive MS and patients with acute relapses, but not in the stable form of the disease. Considering the association of different TNF-α alleles with diverse autoimmune diseases we sequenced the TNF-α promotor region (−674 to +201) of 23 patients with relapsing/remitting MS, of 27 patients with chronic progressive MS (21 patients had primary families. In three of 21 patients (14%) with primary chronic progressive MS a homozygous point-mutation at position −308 could be demonstrated where guanine (G) was substituted by adenosine (A). This mutation could neither be detected in patients with relapsing/ remitting MS nor in healthy controls. However, 40% of the patients with relapsing/remitting MS and 43% of the primary chronic progressive MS patients were heterozygous at position −308 for G/A, whereas only 32% of healthy controls showed this heterogeneity. The genetic variations were demonstrated by polymerase chain reaction (PCR) -amplification of the TNF-α promotor-region and consecutive direct automatic sequencing. Functional analysis of the promoter region using the chloramphenicol-acetyltransferase (CAT) assay revealed spontaneous production with the homozygous mutation at −308 only.