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

Christina Mary Mariaselvam Salah Sofiane

doi:10.4172/2155-9929.1000206

Abstract

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.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint damage and destruction
We found that the distribution of the TNF-α -238G allele and GG genotype was higher in patients as compared to healthy controls (G vs A: 93% vs 87%, Pc=0.004, odds ratio (OR)=1.89, 95% confidence interval (95%CI) = 1.21-2.97 and GG vs GA+AA: 87% vs 76%, Pc= 0.004, OR= 2.01, 95%CI = 1.23-3.29 in patients and healthy controls respectively) (Table 1)
We found that the TNF rs1799724 and rs361525 were in strong linkage disequilibrium (Figure 1).Color scheme of the LD map is based on the standard D'/LOD option in the Haploview software

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint damage and destruction. Functional studies of TNF-α polymorphism have indicated its association with different TNF-α expression profiles and circulating TNF-α levels [9,10,11] These polymorphisms in TNF-α promoter region may influence TNF-α production, which in turn may have an impact on inflammatory responses, disease expression and response to therapy. Taking advantage of a phenotypically well-defined and ethnically homogeneous South Indian Tamil RA population of Dravidian descent, we conducted a case-control study to analyze whether three functionally relevant TNF-α promoter SNPs i.e. TNF-α -857, -308 and -238 could influence RA susceptibility, disease phenotype, TNF-α production or response to therapy with synthetic disease modifying anti-rheumatic drugs (DMARDs)

Materials and Methods

Results

Discussion and Conclusion