Zur Bedeutung des SNP309 des Mdm2-Gens für die CVID und die rheumatoide Arthritis

Abstract

A single nucleotide polymorphism (exchange of a single base) in the prormoter region of the Mdm2 gene (SNP309) was first described in 2004. It was shown that the change from Thymine to Guanine at position 309 of the first intron caused a higher affinity of the Mdm2 promoter for transcription factor Sp1. Thus Mdm2 transcription is facilitated. Mdm2 is well known as one of the most important negative regulators of the tumor suppressor p53. Accordingly, an increased synthesis of Mdm2 suppresses cellular p53 signalling. The consequence is, that DNA-damaged cells are less efficiently repaired or eliminated and are thus more prone to tumor development. In addition p53 serves as an antagonist of NfκB, the transcription factor determining the course of inflammations. P53 suppression therefore causes a more sensitive reaction towards inflammatory reaction. We therefore asked whether p53 suppression caused by SNP309 could be associated with the development of chronic inflammations, especially of chronic inflammations linked with an increased activity of NfκB. Rheumatoid Arthritis and lymphadenophathy, splenomegaly and granulomatous disease in patients with CVID (common variable immunodeficiency) were chosen as examples for such inflammatory diseases. First the SNP309 genotype distribution among Europeans was analysed. The results obtained, failed to differ from those in North Americans described by the group that discovered the polymorphism (p = 0,299). The genotype distribution among 52 patients with CVID (p = 0,743) showed also no difference compared with healthy Europeans. Similarly no association of lymphadenopathy (p = 0,282), splenomegaly (p = 0,806) and granulomatous disease (p = 0,422) in CVID patients with the SNP309 was detectable. Interestingly, the SNP309 was less often detected in patients with Rheumatoid Arthritis as in healthy people (healthy people: G/T 49,3 %, G/G 14,2 %; patients with RA: G/T 42,2 %, G/G 10,9 %; p= 0,046). Gender-dependent stratification showed that the differences were caused by the genotype distribution among female patients (p = 0,043). No differences were detected between the genotype distributions in males (p = 0,577). Increased Mdm2-levels might thus