Association of rheumatoid arthritis with Mdm2 SNP309 and genetic evidence for an allele-specific interaction between MDM2 and p53 P72R variants: a case control study.
OBJECTIVE
This study examines two common, functional, single nucleotide polymorphisms (SNP) in the genes coding the human homolog of murine-double-minute-2 (MDM2) and p53 in patients with rheumatoid arthritis (RA) based on the hypothesis that p53 may be an important negative regulator of the pro-inflammatory transcription factor nuclear factor kappa b (NFKappaB).


METHODS
Genomic DNA was obtained from 221 patients with RA who fulfilled at least 4 ACR criteria and from 521 healthy controls. Mdm2 SNP309 and p53 P72R were genotyped by polymerase chain reaction and restriction enzyme analysis.


RESULTS
In RA patients the frequencies of the mdm2 SNP309 G allele and both G-containing genotypes were significantly reduced (G allele: OR: 0.75, 95% CI: 0.59-0.95, p=0.016; genotype TG: OR: 0.71, 95% CI: 0.50-1.00; genotype GG: OR. 0.58, 95% CI: 0.34-0.99; both: p=0.049). Concerning p53 P72R, no differences in allele or genotype frequencies were detected. A combined analysis of both polymorphisms revealed a significant interaction between them (p=0.046). In individuals carrying >1 p53 72R allele, MDM2 had a protective effect, whereas in individuals homozygous for p53 72P, MDM2 had the opposite effect.


CONCLUSIONS
The function of MDM2 depends on the p53 P72R genotype, resulting in either an increased or reduced risk for RA. We suggest that in most cases MDM2 stabilizes the conformation of p53, whereas in p53 PP-positive subjects MDM2 supports the degradation of p53.
Assmann
G
G
Internal Medicine I and José-Carreras-Research Center, University of Saarland Medical School, Homburg/Saar, Germany. gunter.assmann@uniklinikumsaarland.de
Voswinkel
J
J
Mueller
M
M
Bittenbring
J
J
Koenig
J
J
Menzel
A
A
Pfreundschuh
M
M
Roemer
K
K
Melchers
I
I
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2