Lack of Association of the TP53 Arg72Pro SNP and the MDM2 SNP309 with systemic lupus erythematosus in Caucasian,African American,and Asian children and adults

Abstract

The p53 tumour suppressor is the central regulator of apoptosis. Previously, the functional TP53 Arg72Pro polymorphism was found to be associated with systemic lupus erythematosus (SLE) in Koreans but not Spaniards. MDM2 is the major negative regulator of p53. An intronic polymorphism in MDM2, the SNP309, attenuates p53 activity and is associated with accelerated tumour development in premenopausal women. Polymorphic variation in MDM2 has never been studied in SLE. The aim of this study is to further assess the contribution of p53-pathway genetic variation to SLE by testing the association of the TP53 Arg72Pro polymorphism and the MDM2 SNP309 with SLE in a well-characterised and ethnically diverse cohort of patients with both childhood- and adult-onset SLE (n = 314). No association was found between the TP53 Arg72Pro polymorphism and SLE in patients of European descent, Asian descent or in African Americans, nor was an association found between the MDM2 SNP309 and SLE in patients of European descent or in African Americans. In addition, there was no correlation between either variant and early-onset disease or nephritis, an index of severe disease. It is concluded that neither the TP53 Arg72Pro polymorphism nor the MDM2 SNP309 contributes significantly to either susceptibility or disease severity in SLE.

Keywords

genetic polymorphism nephritis pediatrics systemic lupus erythematosus

References

1 Tsao BP . Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol 2004; 16: 513–521.

2 Lorenz HM Herrmann M Winkler T Gaipl U Kalden JR . Role of apoptosis in autoimmunity. Apoptosis 2000; 5: 443–449.

3 Gaipl US Munoz LE Grossmayer G . Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun 2007; 28: 114–121.

4 Vogelstein B Lane D Levine AJ . Surfing the p53 network. Nature 2000; 408: 307–310.

5 Bose I Ghosh B . The p53-MDM2 network: from oscillations to apoptosis. J Biosci 2007; 32: 991–997.

6 Dumont P Leu JI Della Pietra AC George DL Murphy M . The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 2003; 33: 357–365.

7 Bond GL Hu W Bond EE . A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004; 119: 591–602.

8 Lee YH Rho YH Choi SJ Ji JD Song GG . The functional p53 codon 72 polymorphism is associated with systemic lupus erythematosus. Lupus 2005; 14: 842–845.

9 Sanchez E Sabio JM Callejas JL . Study of a functional polymorphism in the p53 gene in systemic lupus erythematosus: lack of replication in a Spanish population. Lupus 2006; 15: 658–661.

10.

10 Bond GL Levine AJ . A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 2007; 26: 1317–1323.

11.

11 Elkon KB . Apoptosis and SLE. Lupus 1994; 3: 1–2.

12.

12 Nath SK Kelly JA Namjou B . Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet 2001; 69: 1401–1406.

13.

13 El-Sayed ZA Farag DH Eissa S . Tumor suppressor protein p53 and anti-p53 autoantibodies in pediatric rheumatological diseases. Pediatr Allergy Immunol 2003; 14: 229–233.

14.

14 Bond GL Hirshfield KM Kirchhoff T . MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 2006; 66: 5104–5110.

15.

15 Harley JB Alarcon-Riquelme ME Criswell LA . Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008; 40: 204–210.