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Systemic Lupus Erythematosus (SLE) is a clinically heterogeneous chronic, inflammatory autoimmune disorder that affects multiple organs where exact etiology of the disease is not yet clearly understood. Various evidences suggest that genetic polymorphisms in inflammatory mediators like cytokines and chemokines may influence development of the disease. Here, we investigated whether functional polymorphism at the Monocyte Chemoattractant Protein-1 (MCP-1) regulatory region associates with disease phenotype in Indian SLE patients. This case control study included 200 SLE patients and 201 ethnically matched healthy controls. Genotyping of MCP-1 (−2518 A/G) polymorphism was performed using PCR-RFLP method. Serum MCP-1 levels were detected by bead-based multiplex immunoassay. Serum MCP-1 levels were found to be higher in patients compared with healthy individuals (p < 0.0001). A significant difference for MCP-1G allele frequency (OR = 1.9, 95%CI = 1.4–2.6, p < 0.0001) was observed among SLE patients against healthy individuals. A significant difference in the distribution of MCP-1 −2518GG (OR = 3.0, 95%CI = 1.4–6.7, p = 0.0041) and AG + GG genotypes (OR = 2.0, 95%CI = 1.4–3.0, p = 0.0005) was also noted among SLE patients when compared with healthy individuals. A significant association was observed between A/G and G/G versus A/A genotypes with renal manifestations (p < 0.0001, Pc < 0.001). Serum MCP-1 levels in active LN patients were found to be significantly higher than inactive LN (p = 0.0059), mild LN (p = 0.0061) as well as non-LN patients (p = 0.0001). These findings suggest that −2518G allele of MCP-1 −2518 A/G polymorphism is associated with renal disorders and may influence MCP-1 gene expression among Indian SLE patients.