Molecular Biomarkers & Diagnosis

TNF alpha Promoter Polymorphism May Confer Susceptibility to Rheumatoid Arthritis and Influence TNF alpha Production but not the Clinical Phenotype and Treatment Response

Abstract

Christina Mary Mariaselvam, Salah Sofiane, Wahid Boukouaci, Catherine Fortier, Dominique Charron, Rajagopal Krishnamoorthy, Ryad Tamouza and Vir Singh Negi

Rheumatoid arthritis (RA) is characterized by progressive joint damage predominantly mediated by proinflammatory molecules including the tumor necrosis factor alpha (TNF-α). Several studies have addressed the relationship between diversity of TNF-α gene and susceptibility to RA and its clinical phenotypes but the results have been inconsistent. We conducted a case-control study to analyze the potential influence of three functionally relevant TNF-α promoter variants on RA incidence and disease phenotypes and serum TNF-α levels in a genetically homogeneous south Indian Tamil population. Genomic DNA from 269 RA patients and 233 healthy controls (HC) were analyzed by TaqMan 5’-nuclease assay for the distribution of the following SNPs: TNF-α -857 C>T (rs1799724), TNF-α -308 G>A (rs1800629) and TNF-α -238 G>A (rs 361525). We found that the frequency of the TNF-α -238 GG genotype and G allele was higher in patients as compared to controls [Pc: 0.004, OR: 2.01, CI 95%: 1.23-3.29 and Pc: 0.004, OR: 1.89, CI 95%: 1.22-2.97 respectively]. The genotype and allele frequency of TNF-α -857 C>T and -308 G>A polymorphisms did not differ between patients and controls. Haplotype analysis revealed that the frequency of ancestral TNF-α (-857,-308,-238) C-G-G haplotype was more in patients than in HC (80% vs 74%, P: 0.03, OR: 1.39, CI 95%: 1.02-1.89). The CGA haplotype was found at a higher frequency in HC than in patients (10.6% vs 7%, P: 0.03, OR: 0.61, CI 95%: 0.38-0.96). We also found that TNF-α-857T allele was associated with significantly high titers of circulating TNF-α. Our data suggest that TNF-α -238 G allele, -238 GG genotype and the TNF-α –C-G-G ancestral haplotype may be associated with susceptibility to RA. In addition, the TNF-α-857 C>T variant might influence the TNF-α production.