Association of the TLR4 gene single nucleotide polymorphism rs2149356 and susceptibility to developing Rheumatoid Arthritis

Abstract

Introduction: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease that predominantly affects the synovial membrane, characterized by symmetrical polyarticular deterioration involving both small and large joints. The etiology of RA is multifactorial, including genetic factors; currently, studies are underway regarding the role of single nucleotide polymorphisms (SNPs) and their association with RA. Toll-like receptors (TLRs) are known to play important roles in the immune system, and their association with the development of RA has been demonstrated. Yan Wang reported in 2017 that the association of the TLR4 gene SNP rs41426344 increases susceptibility to RA in a Chinese population. However, to date, there are no specific studies of the TLR4 gene SNP rs2149356 and its association with RA, particularly in the Mexican population.

Objective: To determine the association between the rs2149356 single nucleotide polymorphism of the TLR4 gene and susceptibility to developing rheumatoid arthritis (RA).

Methodology: The study was conducted in a Mexican population of men and women, including 112 patients with RA and 76 controls, all with at least two generations of Mexican ancestry. The RA patients met the classification criteria of the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR). A three-element blood chemistry panel (glucose, cholesterol, and triglycerides) was performed, and a sociodemographic questionnaire was administered. The rs2149356 SNP of the TLR4 gene was analyzed; the association analysis was adjusted for age and sex. Allelic discrimination was analyzed using StepOne v2.3 software. Statistical comparisons were performed using Student's t-test, with a p-value <0.05 considered statistically significant.

Results: The analyzed variables showed that patients were older than controls, with mean ages of 54.45 ± 12.66 and 46.47 ± 15.91 years, respectively (P = 0.0002). Triglyceride, cholesterol, and glucose levels did not differ significantly between the study groups. The genotypic frequencies observed in the study groups were consistent with those expected according to Hardy-Weinberg equilibrium analysis (p > 0.05). Preliminary data show that in our total study population, the TLR4 gene SNP rs2149356 was significantly associated with rheumatoid arthritis (RA) after adjusting for age and sex. Under the dominant model, carriers of at least one T allele (G/T–T/T) had a lower probability of response compared to G/G individuals (OR = 0.42; 95% CI: 0.20–0.86; p = 0.016). Consistent results were observed in the codominant (OR = 0.40; 95% CI: 0.19–0.85; p = 0.049), superdominant (OR = 0.43; 95% CI: 0.21–0.89; p = 0.02), and log-additive (OR = 0.55; 95% CI: 0.31–0.98; p = 0.04) models.

Conclusions: These findings suggest that the presence of the T allele is associated with a lower probability of developing rheumatoid arthritis in our study population.