A recent study published in the International Journal of Immunogenetics has identified a strong association between the CC genotype of the Toll-like receptor 4 (TLR4) rs41426344 polymorphism and increased susceptibility to ankylosing spondylitis (AS), along with higher disease activity, in a Turkish population. The findings add to growing evidence that genetic variation in innate immune pathways plays a significant role in the pathogenesis and clinical expression of inflammatory arthritis.
The case–control study included 200 participants, comprising 100 patients with clinically diagnosed ankylosing spondylitis and 100 age- and sex-matched healthy controls. Genotyping of the TLR4 rs41426344 (G/C) polymorphism was performed using real-time polymerase chain reaction melting curve analysis. Disease activity and functional status were evaluated using validated clinical indices, including the Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP).
The CC genotype showed a very strong association with AS susceptibility, with carriers demonstrating a tenfold increased risk of disease compared with other genotypes (odds ratio 10.00; 95% confidence interval 4.091–24.431; p < 0.0000001). In addition to higher susceptibility, patients with the CC genotype exhibited significantly elevated BASFI, BASDAI, and ASDAS-CRP scores, reflecting greater functional impairment, higher symptom burden, and increased systemic inflammation. A statistically significant difference in ASDAS-CRP scores was also observed between CC and GC genotypes, further supporting the link between this variant and disease severity.
These results are consistent with previous findings in other inflammatory arthritides. In a central south Chinese Han population, the rs41426344C allele was previously associated with increased susceptibility to both rheumatoid arthritis and juvenile idiopathic arthritis, with higher odds of disease among carriers and increased frequency of the variant in rheumatoid factor–positive and anti–cyclic citrullinated peptide–positive patients. Together, these observations suggest that the rs41426344C variant may represent a shared genetic risk factor across multiple immune-mediated inflammatory diseases.
This is the first report examining the TLR4 rs41426344 polymorphism in ankylosing spondylitis. TLR4 plays a central role in innate immune activation by recognizing pathogen-associated molecular patterns and triggering downstream pro-inflammatory signaling pathways. Genetic variation in this receptor may amplify inflammatory responses, contributing to both increased disease susceptibility and more aggressive clinical phenotypes.
From a clinical perspective, the findings indicate that the TLR4 rs41426344 CC genotype may serve as a potential biomarker for disease risk assessment and activity monitoring in ankylosing spondylitis, particularly in Turkish patients. Validation in larger, multi-ethnic cohorts and functional studies will be necessary to determine how this variant alters TLR4 signaling and whether it can be incorporated into future precision medicine strategies for spondyloarthritis.
References
- Kirkik D, Kalkanli Tas S, Dogantekin B, Kariksiz M, Gündogdu B, Hacimustafaoglu F, Aksoy R. The Impact of TLR4 rs41426344 Polymorphism on Ankylosing Spondylitis Disease Activity: A Study in Turkish Patients. Int J Immunogenet. 2026 Feb;53(1):54-62.
- Wang Y, Chen L, Li F, Bao M, Zeng J, Xiang J, Luo H, Li J, Tang L. TLR4 rs41426344 increases susceptibility of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) in a central south Chinese Han population. Pediatr Rheumatol Online J. 2017 Feb 21;15(1):12.