TP53 and P21 (CDKN1A) Polymorphisms and the Risk of Systemic Lupus Erythematosus

Overview

Journal Adv Rheumatol

Publisher Biomed Central

Specialty Rheumatology

Date 2023 Aug 22

PMID 37605254

Authors

Jacyara Maria Brito Macedo

Amanda Lima Silva

Amanda Chaves Pinto

Leandro Ferreira Lopes Landeira

Elyzabeth Avvad Portari

Cintia Barros Santos-Reboucas

Evandro Mendes Klumb

Affiliations

Soon will be listed here.

Abstract

Background: The p53 and p21 proteins are important regulators of cell cycle and apoptosis and may contribute to autoimmune diseases, such as systemic lupus erythematosus (SLE). As genetic polymorphisms may cause changes in protein levels and functions, we investigated associations of TP53 and p21 (CDKN1A) polymorphisms (p53 72 G > C-rs1042522; p53 PIN3-rs17878362; p21 31 C > A-rs1801270; p21 70 C > T-rs1059234) with the development of systemic lupus erythematosus (SLE) in a Southeastern Brazilian population.

Methods: Genotyping of 353 female volunteers (cases, n = 145; controls, n = 208) was performed by polymerase chain reaction, restriction fragment length polymorphism and/or DNA sequencing. Associations between TP53 and p21 polymorphisms and SLE susceptibility and clinical manifestations of SLE patients were assessed by logistic regression analysis.

Results: Protective effect was observed for the genotype combinations p53 PIN3 A1/A1-p21 31 C/A, in the total study population (OR 0.45), and p53 PIN3 A1/A2-p21 31 C/C, in non-white women (OR 0.28). In Whites, p53 72 C-containing (OR 3.06) and p53 PIN3 A2-containing (OR 6.93) genotypes were associated with SLE risk, and higher OR value was observed for the combined genotype p53 72 G/C-p53 PIN3 A1/A2 (OR 9.00). Further, p53 PIN3 A1/A2 genotype was associated with serositis (OR 2.82), while p53 PIN3 A2/A2 and p53 72 C/C genotypes were associated with neurological disorders (OR 4.69 and OR 3.34, respectively).

Conclusions: Our findings showed that the TP53 and p21 polymorphisms included in this study may have potential to emerge as SLE susceptibility markers for specific groups of patients. Significant interactions of the TP53 polymorphisms with serositis and neurological disorders were also observed in SLE patients.

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References

Sharabi A, Tsokos G . T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Nat Rev Rheumatol. 2020; 16(2):100-112. DOI: 10.1038/s41584-019-0356-x. View

Pan L, Lu M, Wang J, Xu M, Yang S . Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr. 2019; 16(1):19-30. PMC: 7040062. DOI: 10.1007/s12519-019-00229-3. View

Gupta S, Kaplan M . The role of neutrophils and NETosis in autoimmune and renal diseases. Nat Rev Nephrol. 2016; 12(7):402-13. PMC: 5510606. DOI: 10.1038/nrneph.2016.71. View

Gaipl U, Munoz L, Grossmayer G, Lauber K, Franz S, Sarter K . Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun. 2007; 28(2-3):114-21. DOI: 10.1016/j.jaut.2007.02.005. View

Zhao Y, Wei W, Liu M . Extracellular vesicles and lupus nephritis - New insights into pathophysiology and clinical implications. J Autoimmun. 2020; 115:102540. PMC: 9107953. DOI: 10.1016/j.jaut.2020.102540. View

Takatori H, Kawashima H, Suzuki K, Nakajima H . Role of p53 in systemic autoimmune diseases. Crit Rev Immunol. 2015; 34(6):509-16. DOI: 10.1615/critrevimmunol.2014012193. View

Kovacs B, Patel A, Hershey J, Dennis G, Kirschfink M, Tsokos G . Antibodies against p53 in sera from patients with systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum. 1997; 40(5):980-2. DOI: 10.1002/art.1780400531. View

Joruiz S, Bourdon J . p53 Isoforms: Key Regulators of the Cell Fate Decision. Cold Spring Harb Perspect Med. 2016; 6(8). PMC: 4968168. DOI: 10.1101/cshperspect.a026039. View

Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J . TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data. Hum Mutat. 2016; 37(9):865-76. DOI: 10.1002/humu.23035. View

10.

Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G . Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol. 1999; 19(2):1092-100. PMC: 116039. DOI: 10.1128/MCB.19.2.1092. View

11.

Senturk E, Manfredi J . p53 and cell cycle effects after DNA damage. Methods Mol Biol. 2012; 962:49-61. PMC: 4712920. DOI: 10.1007/978-1-62703-236-0_4. View

12.

Gemignani F, Moreno V, Landi S, Moullan N, Chabrier A, Gutierrez-Enriquez S . A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA. Oncogene. 2003; 23(10):1954-6. DOI: 10.1038/sj.onc.1207305. View

13.

Lawson B, Baccala R, Song J, Croft M, Kono D, Theofilopoulos A . Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. J Exp Med. 2004; 199(4):547-57. PMC: 2211831. DOI: 10.1084/jem.20031685. View

14.

Kong E, Chong W, Wong W, Lau C, Chan T, Ng P . p21 gene polymorphisms in systemic lupus erythematosus. Rheumatology (Oxford). 2006; 46(2):220-6. DOI: 10.1093/rheumatology/kel210. View

15.

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

16.

Li G, Liu Z, Sturgis E, Shi Q, Chamberlain R, Spitz M . Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis. 2005; 26(9):1596-602. DOI: 10.1093/carcin/bgi105. View

17.

Yang J, Zhu J, Wu S, Li J, Wang M, Wang T . Association study between the TP53 Rs1042522G/C polymorphism and susceptibility to systemic lupus erythematosus in a Chinese Han population. Rheumatol Int. 2017; 37(4):523-529. DOI: 10.1007/s00296-017-3662-0. View

18.

Hochberg M . Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40(9):1725. DOI: 10.1002/art.1780400928. View

19.

Pena S, Di Pietro G, Fuchshuber-Moraes M, Genro J, Hutz M, Kehdy F . The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS One. 2011; 6(2):e17063. PMC: 3040205. DOI: 10.1371/journal.pone.0017063. View

20.

Vargas-Torres S, Portari E, Klumb E, da Rocha Guillobel H, de Camargo M, Bastos Russomano F . Association of CDKN2A polymorphisms with the severity of cervical neoplasia in a Brazilian population. Biomarkers. 2014; 19(2):121-7. DOI: 10.3109/1354750X.2014.881419. View