Synergetic Interaction of HLA-DRB1*07 Allele and TNF-Alpha - 863 C/A Single Nucleotide Polymorphism in the Susceptibility to Systemic Lupus Erythematosus.

Abstract

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease which is characterized by dysregulation of various cytokines propagating the inflammatory processes that is responsible for tissue damage. Tumor necrosis factor alpha (TNF-α) is one of the most important immunoregulatory cytokines that has been implicated in the different autoimmune diseases including SLE. Two hundred and two patients with SLE and 318 controls were included in the study. The TNF-α gene promoter region (from - 250 to - 1000 base pairs) was analyzed by direct Sanger's DNA sequencing method to find promoter variants associated with South Indian SLE patients. We have analyzed six TNF-α genetic polymorphisms including, - 863C/A (rs1800630), - 857C/T (rs1799724), - 806C/T (rs4248158), - 646G/A (rs4248160), - 572A/C (rs4248161) and - 308G/A (rs1800629) in both SLE patients and controls. We did not find association of TNF-α gene promoter SNPs with SLE patients. However, the - 863A (rs1800630) allele showed association with lupus nephritis phenotype in patients with SLE (OR: 1.62, 95%CI 1.04-2.53, P = 0.034). We found serum TNF-α level was significantly elevated in SLE cases as compared to control and found no association with any of the polymorphisms. The haplotype analysis revealed a significant protective association between the wild TNF-α alleles at positions - 863C, - 857C, - 806C, - 646G, - 572A and - 308G (CCCGAG) haplotype with lupus nephritis phenotype (OR 0.53, 95% CI 0.35-0.82, P = 0.004). Additionally, the TNF-α - 863 C/A (rs1800630) polymorphism and HLA-DRB1*07 haplotype showed significant differences between SLE patients and controls (OR 4.79, 95% CI 1.73-13.29, P = 0.0009). In conclusion, TNF-α - 863A allele (rs1800630) polymorphism is associated with increased risk of nephritis in South Indian SLE patients. We also found an interaction between HLA-DRB1*07 allele with TNF-α - 863 C/A promoter polymorphism giving supportive evidence for the tight linkage disequilibrium between TNF-α promoter SNPs and MHC class II DRB1 alleles.