Association of TNF-alpha Promoter Polymorphisms with Disease Susceptibility, mRNA Expression, and Lupus Nephritis in Mexican Patients with Systemic Lupus Erythematosus

<b>Background/Objectives</b>: A case-control study was conducted to determine the association of the -238 G>A and -308 G>A <i>TNF-alpha</i> (<i>TNFA</i>) promoter polymorphisms with mRNA and protein expression in 180 Systemic Lupus Erythematosus (SLE) patients and 186 control subjects (CS) from western Mexico. <b>Methods</b>: Genotyping was performed using the PCR-RFLP method. <i>TNFA</i> mRNA expression was assessed by real-time quantitative PCR, and soluble TNF-α (sTNF-α) levels were quantified by ELISA. For comparison groups, Chi-square, Mann-Whitney U, or Kruskal-Wallis tests were used. Spearman's rank correlation coefficient determined the correlation between variables. The Area Under the Curve was used to determine the diagnosing performance of sTNF-α. <b>Results</b>: No differences were found in the genotype distribution of -238 G>A and -308 G>A <i>TNFA</i> polymorphisms between SLE patients and CS. However, the -238A allele was associated with increased SLE susceptibility (OR 1.18 CI 95% 1.02-3.50, <i>p</i> = 0.037). Also, logistic regression analysis showed that LN risk was significantly higher in carriers of the -308A allele (OR 3.11 IC95% 1.15-6.43; <i>p</i> = 0.002). On the other hand, the <i>TNFA</i> mRNA expression was 3.3-fold higher in SLE compared to CS. SLE patients with -308 GG genotype showed higher <i>TNFA</i> mRNA expression compared to GA+AA genotype carriers (<i>p</i> < 0.01). Regarding sTNFa levels, SLE patients showed higher concentration than CS, mainly in lupus nephritis (LN), with a weak negative correlation with estimated Glomerular Filtration Rate and an acceptable accuracy for diagnosing SLE and LN, with areas under the curve of 0.61 and 0.65, respectively. <b>Conclusions</b>: The -238 A allele and -308 A allele of the <i>TNFA</i> gene are linked to a higher risk of susceptibility to SLE and LN in the western Mexican population. Additionally, SLE patients exhibited increased TNF-alpha gene expression and sTNF-α, particularly in LN, demonstrating acceptable diagnostic performance.