MCP-1, RANTES, and SDF-1 polymorphisms in Mexican patients with systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is a chronic and systemic autoimmune disease that is characterized by autoantibody production, abnormalities of immune–inflammatory system function, and inflammatory manifestation in several organs [1]. Genetic factors play an important role in the susceptibility to its development. Particular attention has been focused on the association of disease with genetic markers located within the major histocompatibility complex region on the short arm of chromosome 6. The mechanism by which these genes determine susceptibility is not completely understood and the participation of non-HLA genes has been suggested [2], [3], [4]. In this respect, there are several lines of evidence that chemokines and cytokines play an important role in the inflammatory development and progression of autoimmune diseases such as SLE [5], [6], [7], [8]. According to previous reports, monocyte chemoattractant protein 1 (MCP-1), stromal cell-derived factor-1 (SDF-1), and regulated on activation normal T cell expressed and secreted (RANTES) are candidate chemokines for study in SLE. MCP-1 and RANTES are involved in the physiology and pathophysiology of acute and chronic inflammatory processes by recruitment of monocytes, T lymphocytes, and eosinophils to sites of inflammation [9], [10]. High serum levels of these chemokines have been reported in SLE patients [11]. SDF-1 (CXCL12) is a chemokine that plays an important role in the regulation of migration, proliferation, and differentiation of hematopoietic cells [12], [13]. In the mouse model NZB/W, SDF-1 participates in the chemotaxis, proliferation, and survival of B1a cells, which produce pathogenic autoantibodies directed against nuclear cells, including anti-dsDNA, which carry a lethal nephritis [14]. Several reports suggest that some genetic variants of the genes that code these chemokines can affect the transcriptional activity and subsequent protein expression in humans [15], [16], [17]. In the distal region of the MCP-1 gene, a guanine (G) to adenine (A) transition was identified at position -2518 upstream from the major transcription site (MCP-1-2518), and this polymorphism has been associated with circulating MCP-1 levels. When stimulated by IL-1 β, monocytes/macrophages from homozygous G/G individuals produce up to 1.7 times more MCP-1 than those homozygous for A/A [15]. A genetic polymorphism exists in the nontranslated 3′ region (3′UTR) of gene SDF-1 in position 801, which seems to increase the amount of SDF-1 messenger RNA, with an apparently protective effect against rapid progression toward AIDS [18]. The RANTES-28 polymorphism has a modest effect on the increase of the transcription of the gene [19] and has been associated with high initial levels of antinuclear antibodies (ANAs), low levels of C3, and a high incidence of neuropsychiatric lupus in Chinese children with SLE [20]. Also, some of these polymorphisms have been analyzed in case–control studies in SLE patients with heterogeneous results in different populations [5], [6], [21], [22], [23]. Thus, the aim of the present study was to investigate the role of MCP-1, SDF-1, and RANTES polymorphisms as contributors to genetic susceptibility and clinical manifestation of the SLE in Mexican Mestizo patients.
Section snippets
Studied population
The study included 242 unrelated SLE Mexican patients, 220 women and 22 men. All patients fulfilled at least four of the American College of Rheumatology criteria for SLE [24]. One hundred twenty-one of the patients showed lupus nephritis, 73 (60.3%) of which were confirmed with biopsy. The no-biopsy group satisfied at least four of the following criteria: (i) creatinine clearance < 70 mL/minute, (ii) proteinuria greater than 1 g/24 hours, (iii) granular and erythrocytic casts in urine, (iv)
Results
A total of 242 patients with SLE diagnosis were included in the study (220 women and 22 men). Demographical and clinical characteristics of the studied patients are shown in Table 1. Clinical manifestations were presented at least once during the evolution period of the disease, measured from the time of diagnosis to the moment when a blood sample was drawn.
Allele and genotype frequencies of MCP-1-2518, SDF-1 G801A, and RANTES-28 polymorphisms in SLE patients and healthy controls are shown in
Discussion
Several lines of evidence suggest that chemokines and cytokines play an important role in the inflammatory process and progression of SLE [6], [7], [8]. Chemokines such as MCP-1, SDF-1, and RANTES have been involved in inflammatory pathologies. In the present study, we assessed the association between MCP-1-2518, SDF-1 G801A, and RANTES-28 polymorphisms and the genetic susceptibility to developing SLE in a group of Mexican patients. The relationship between these polymorphisms and
Acknowledgments
The authors are grateful to the study participants. Institutional review board approval was obtained for all sample collections.
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