The codon 72 polymorphic variants of p53 in Italian rheumatoid arthritis patients.

OBJECTIVE The p53 tumor suppressor protein plays an important role in cell apoptosis. The wild type p53 protein presents a common polymorphism at position 72 resulting in either a proline or an arginine residue at this position, leading to differences between the two variants in the induction of apoptosis. We examined the possible associations of this polymorphism with the occurrence of rheumatoid arthritis (RA) and its severity in a series of RA patients of Italian origin. METHODS 170 consecutive RA patients fulfilling the 1997 ACR criteria and seen over a 4-month period in our rheumatology centre were studied. The medical records of the patients were reviewed for demographic and clinical parameters. Radiographs of the hands and feet taken at disease onset and after 5 years were available for 122 of the patients and were used to determine the presence and number of erosions, which were scored according to the modified Sharp/van der Heijde method (S/vdH). All of the RA patients and controls were genotyped by the polymerase chain reaction and allele-specific oligonucleotide techniques for p53 gene polymorphism Arg/Pro at codon 72. RESULTS The distribution of the polymorphism of Arg/Pro 72 did not differ significantly between patients and healthy controls (Arg/Arg 47.1 vs 48.5%, Arg/Pro 43.5% vs 42%, Pro/Pro 9.8 vs 9.5% respectively, p=ns). Patients carrying the Pro/Pro genotype had a significantly higher percentage of erosive disease at year 5 compared with patients carrying the Arg/Arg genotype (Pro/Pro 93%, Arg/Arg 52%, p=0.0001). The mean number of eroded joints per patient at 5 years was higher in the Pro/Pro subgroup and significantly lower in the Arg/Arg subgroup (Pro/Pro 13.2, Arg/Arg 3.6, p=0.0001). The mean S/vdH erosive score, joint space narrowing score and total damage score were significantly higher in the Pro/Pro subgroup compared with the Arg/Arg and Arg/Pro subgroups. CONCLUSION In the Italian population there is no association between codon 72-p53 gene polymorphism and the occurrence of RA. However, this polymorphism is associated with the structural damage of the disease.

[1]  D. Green,et al.  Regulation of arthritis by p53: critical role of adaptive immunity. , 2005, Arthritis and rheumatism.

[2]  N. Olsen,et al.  Reduced p53 in peripheral blood mononuclear cells from patients with rheumatoid arthritis is associated with loss of radiation-induced apoptosis. , 2005, Arthritis and rheumatism.

[3]  Hongtao Liu,et al.  Apoptosis in rheumatoid arthritis: friend or foe. , 2004, Rheumatic diseases clinics of North America.

[4]  B. Nakken,et al.  Apoptotic Effect of Rituximab on Peripheral Blood B Cells in Rheumatoid Arthritis , 2004, Scandinavian journal of immunology.

[5]  K. Elkon,et al.  Mechanisms of apoptosis. , 2004, Rheumatic diseases clinics of North America.

[6]  S. Gay,et al.  Apoptosis in rheumatoid arthritis , 2003, Current opinion in rheumatology.

[7]  M. Murphy,et al.  The codon 72 polymorphic variants of p53 have markedly different apoptotic potential , 2003, Nature Genetics.

[8]  G. Kroemer,et al.  Molecular mechanisms of sulfasalazine‐induced T‐cell apoptosis , 2002, British journal of pharmacology.

[9]  T. Strom,et al.  Fibroblast-Like Synoviocytes from Rheumatoid Arthritis Patients Express Functional IL-15 Receptor Complex: Endogenous IL-15 in Autocrine Fashion Enhances Cell Proliferation and Expression of Bcl-xL and Bcl-21 , 2002, The Journal of Immunology.

[10]  D. Green,et al.  Regional analysis of p53 mutations in rheumatoid arthritis synovium , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Y. H. Lee,et al.  p53 codon 72 polymorphism and rheumatoid arthritis. , 2001, Journal of Rheumatology.

[12]  K. Yudoh,et al.  Methotrexate inhibits rheumatoid synovitis by inducing apoptosis. , 2001, The Journal of rheumatology.

[13]  B. Bonavida,et al.  Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. , 2001, Cancer research.

[14]  P. Robbins,et al.  Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[15]  K. Vousden,et al.  Minireviewp 53 : Death Star able to induce the defensive p 53 response to oncogene , 2000 .

[16]  H. Taubert,et al.  The p53 status in juvenile chronic arthritis and rheumatoid arthritis , 2000, Clinical and experimental immunology.

[17]  C. Salvarani,et al.  Intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in Italian patients with rheumatoid arthritis. , 2000, Clinical and experimental rheumatology.

[18]  R. Rodenburg,et al.  The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in macrophages by inducing apoptosis. , 2000, Arthritis and rheumatism.

[19]  H. Hamada,et al.  Differential regulation of Fas-mediated apoptosis of rheumatoid synoviocytes by tumor necrosis factor alpha and basic fibroblast growth factor is associated with the expression of apoptosis-related molecules. , 2000, Arthritis and rheumatism.

[20]  F. Breedveld,et al.  p53 overexpression in synovial tissue from patients with early and longstanding rheumatoid arthritis compared with patients with reactive arthritis and osteoarthritis. , 1999, Arthritis and rheumatism.

[21]  Miranda Thomas,et al.  Two Polymorphic Variants of Wild-Type p53 Differ Biochemically and Biologically , 1999, Molecular and Cellular Biology.

[22]  G. Evan,et al.  A matter of life and cell death. , 1998, Science.

[23]  L. Genestier,et al.  Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. , 1998, The Journal of clinical investigation.

[24]  O. Førre,et al.  Analysis of the NF-kappa B p65 subunit, Fas antigen, Fas ligand and Bcl-2-related proteins in the synovium of RA and polyarticular JRA. , 1998, Clinical and experimental rheumatology.

[25]  G. Firestein,et al.  Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. , 1996, The American journal of pathology.

[26]  U. Müller-Ladner,et al.  Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. , 1996, The Journal of rheumatology.

[27]  S. Yamashita,et al.  Localisation of apoptosis and expression of apoptosis related proteins in the synovium of patients with rheumatoid arthritis. , 1996, Annals of the rheumatic diseases.

[28]  P. Sehgal,et al.  Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP beta (NF-IL6) activity by p53 species. , 1993, The Journal of biological chemistry.

[29]  Jing Yin,et al.  Loss of heterozygosity of p53 in oral cancers demonstrated by the polymerase chain reaction , 1993, Cancer.

[30]  F. Epstein,et al.  Rheumatoid arthritis. Pathophysiology and implications for therapy. , 1990, The New England journal of medicine.

[31]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[32]  D. Pim,et al.  Primary structure polymorphism at amino acid residue 72 of human p53 , 1987, Molecular and cellular biology.

[33]  L. Klareskog,et al.  Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. , 2005, Arthritis and rheumatism.

[34]  G. Haines,et al.  Rheumatoid arthritis synovial macrophages express the Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein and are refractory to Fas-mediated apoptosis. , 2001, Arthritis and rheumatism.

[35]  D. M. van der Heijde,et al.  How to read radiographs according to the Sharp/van der Heijde method. , 2000, The Journal of rheumatology.

[36]  T. Sumida,et al.  Apoptosis in rheumatoid arthritis: a novel pathway in the regulation of synovial tissue. , 1998, Arthritis and rheumatism.

[37]  C. Werning.  [Rheumatoid arthritis]. , 1983, Medizinische Monatsschrift fur Pharmazeuten.