p21 gene polymorphism with systemic lupus erythematosus and rheumatoid arthritis

Professor Lau, Yu Lung   (Principal Investigator (PI))

Professor Lau Wallace Chak Sing   (Co-Investigator)

12

2005-09-01

66150

p21 gene polymorphism with systemic lupus erythematosus and rheumatoid arthritis

p21, rheumatoid arthritis, systemic lupus erythematosus

Allergy/Immunology

200507176012

Small Project Funding

2005

Completed

Systemic lupus erythematosus (SLE ) is a complex, multifactorial autoimmune disease that is characterized by the production of various autoantibodies. Dysregulated T cell-dependent induction of autoreactive B cells is considered to play a critical role in the development of SLE (1). The etiology and pathogenesis of SLE remain unclear, but the increased concordance rate in monozygotic twins, familial aggregation and high heritability suggested that the genetic factor is involved in the development of SLE (2-4). Cyclin-dependent kinase inhibitor 1A (also known as p21, WAF1 or CDKN1A) is a negative regulator of cyclin dependent kinases (CDKs) (5). The p21 protein encodes a 21 kDa cell cycle regulatory protein that forms quaternary complexes with the entire cyclin/CDK holoenzyme and acts as pancyclin inhibitors (6). It interacts with CDK2, CDK3, CDK4 and CDK6, thereby inhibiting the progression from the G1 to the S phase of the cell cycle (7-9). It can also bind to the replication factor proliferating cell nuclear antigen (PCNA) and inhibit DNA replication (10). The p21 gene contains the p53 binding site that is localized at 2.4 kb upstream from the translational start site and expression of p21 gene was found to be inducible by wild-type p53 gene expression (11). Moreover, several growth factors and cytokines, including interferon (IFN)-α and -γ, can modify p21 expression (12,13). As p21 is an important molecule in mediating cell cycle arrest, loss of function in p21 may favor cell proliferation. Mutations in the p21 gene have been reported to associate with development of various cancers (14-17). And cells lacking p21 gene are defective in DNA repair, which might induce impaired regulation in cell proliferation (18). Inactivating mutations of p21 lead to overexpression and hyperactivation of low-avidity, autoreactive T cells that are found in abundance in the peripheral lymphoid organs of normal individuals (19). These findings suggested that dysregulated p21 gene expression might contribute to defective cell cycle regulation and therefore lead to excessive cell proliferation and activation. The human p21 gene maps on chromosome 6p21.2 (11), which is a susceptibility region for SLE (20,21). A significant reduction in p21 gene expression is found in SLE patients as compared to controls (22). A lower expression in SLE patients is detected at various points from the G1 to G2/M phase through the S phase when compared with controls (22). Therefore, malfunction of p21 protein may contribute to the pathogenesis of systemic autoimmunity through a variety of primary or secondary mechanisms. Indeed, the p21-/- female mice with 129/Sv x C57BL/6 mixed backgrounds show development of severe lupus-like diseases followed by early mortality, high levels of anti-dsDNA antibodies and kidney immune complex deposits (23). However, the p21-/- lupus-prone BXSB mice show inhibition for the development of systemic autoimmunity (24). The p21-/- BXSB lupus-prone mice show enhancement of the Fas/FasL-mediated activation-induced T cell death and therefore promote the apoptosis of the accumulated autoreactive T and B cells, which inhibit spontaneous systemic autoimmunity (24). Although the above findings showed conflicting results for p21 deficiency, they suggested p21 gene is involved in the pathogenesis of SLE. Similar to SLE, rheumatoid arthritis (RA) is also a complex autoimmune diseases that involves genetic factors. Although disease pathogenesis remains unclear, we have previously identified the mannose binding lectin (MBL) gene as susceptibility gene in both SLE and RA (25-27) and recently, we have demonstrated that the low producing genotype of IL-10 promoter is associated with disease susceptibility and serositis in Hong Kong Chinese patients with SLE (28). The identification of susceptibility allele in SLE and RA by case-control study offers the potential for early prediction of risk of disease progression. This should also provide an approach to select the most appropriate candidate genes for intervention with new biological agents which may prevent or arrest disease progression in those at highest risk. References: Please refer to attachment [05-CRCG-SLE-References.doc]