The Effect of TNF-Alpha Gene Polymorphisms At -376 G/A, -806 C/T, and -1031 T/C on The Likelihood of Becoming a Non-Responder to Etanercept in A Sample of Iraqi Rheumatoid Arthritis Patients

Abstract

Tumor necrosis factor-alpha (TNF-α) antagonists’ therapy are expensive and has a non-responsive rate between 30% to 40% in rheumatoid arthritis patients. Genetic variation plays a vital role in the responsiveness to this type of therapy.The aim of this study is to investigate if the presence of genetic polymorphism in the TNF-α gene promoter region at locations -376 G/A (rs1800750), -806 C/T (rs4248158), and -1031 T/C (rs1799964) affects rheumatoid arthritis patient's tendency to be a non-responder to etanercept. Eighty RA patients on etanercept (ETN) for at least six months were recruited from the Rheumatology Unit at Baghdad Teaching Hospital. Based on The European League Against Rheumatism response (EULAR) criteria, patients were divided into two groups: responders and non-responders. After polymerase chain reaction amplification of their DNA, the amplified DNA was sequenced by Sanger method to determine the polymorphisms at the positions -376G/A, -806 C/T, and -1031T/C. The results of this study found that equally Phi correlation and binary logistic regression analysis revealed a non-significant association for all genotypes in the three polymorphic sites with the tendency for being non-responder. Moreover, there was no significant difference in TNF-α mean level or the change in disease activity score for 28 joints (DAS28) after six months of etanercept therapy between all genotypes for each polymorphic site. The present study concludes that there was no correlation between the polymorphisms in the TNF-α promoter region at -376G/A, -806 C/T, and -1031T/C with the tendency for being non-responder to ETN.

The Association of Genetic Polymorphisms in Tumor Necrosis Factor-Alpha and Interleukins with Disease Severity or Response to Biological Therapy in Iraqi Rheumatoid Arthritis Patients: A Narrative Review

“…The response to etanercept was greatly enhanced by the GG genotype of -308 G/A and the AA genotype of -863C/A [8]. The tendency to not respond to etanercept was not correlated with the polymorphisms in the TNF-α promoter region at -376G/A, -806 C/T, and -1031T/C [15]. The TNF-α 308 SNP is not correlated with RA in the Iraqi population, according to another study [16].…”

“…This correlation was not supported by subsequent investigations, the findings of which revealed a tenuous correlation in various population studies [59][60][61]. According to an Iraqi study [15] on the prevalence of -1031T/C genotypes, more than 68% of patients had the TT genotype whereas just 3.75% of patients have the CC genotype. However, no statistically significant link between etanercept responsiveness and the -1031T/C polymorphism was found by the analysis.…”

“…However, no statistically significant link between etanercept responsiveness and the -1031T/C polymorphism was found by the analysis. It's interesting to note that no prior studies have examined how 1031T/C affects RA patients' responsiveness to etanercept [15]. The TNF-α-376G/A SNPs may have functional significance and affect TNF-α gene expression levels, even though numerous experimental studies have been carried out to examine the relationship between TNF-α polymorphisms and its expression as well the mechanisms governing its expression in a variety of cell types and diseases [61,62,63].…”

“…The impact of the TNF-α-376 G/A polymorphism on increased susceptibility to RA is unknown because they haven't garnered much attention in RA patients [64,55]. According to Mohammed et al study in Iraq [15], 95% of patients had the genotype GG, 5% had the genotype GA, and there were no homozygotes for the genotype AA. The G allele was found in all people, while the A allele was only found in 5% of RA patients.…”