Impaired telomere maintenance in rheumatoid arthritis: a case-control study of telomerase reverse transcriptase and telomeric repeat-binding factors in disease susceptibility and functional impairment.

OBJECTIVES: To determine the association of telomere-associated proteins, including telomerase reverse transcriptase (TERT), telomeric repeat-binding factor 1 (TERF1), and telomeric repeat-binding factor 2 (TERF2), with rheumatoid arthritis (RA) susceptibility, disease activity, and functional impairment.
METHODS: This case-control study was conducted from March 2025 to February 2026 at the Department of Biochemistry, Islamic International Medical College, Riphah International University, Islamabad, in collaboration with Foundation University, Islamabad, and the Rheumatology Department of a Fauji Foundation Hospital, Rawalpindi. A non-probability purposive sampling technique was used to enroll 66 female patients with RA diagnosed according to the American College of Rheumatology (ACR) classification criteria and 22 age-matched healthy female controls. Disease activity and functional status were assessed using the Clinical Disease Activity Index (CDAI) and Modified Health Assessment Questionnaire (MHAQ). Serum levels of TERT, TERF1, and TERF2 were measured using enzyme-linked immunosorbent assay. Statistical analysis, including group comparisons, correlation, linear regression, binary logistic regression, and mediation analysis, was performed using SPSS version 21.
RESULTS: Binary logistic regression analysis demonstrated that TERT (OR = 7.35, 95% CI, 1.63-33.15, p = 0.009) and TERF2 (OR = 11.04, 95% CI, 2.68-45.50, p = 0.001) were significantly associated with RA susceptibility. Correlation analysis showed weak and non-significant associations of TERT and TERF2 with disease activity and functional disability (r =  - 0.011, p = 0.929) (r = 0.175, p = 0.163) and functional disability (r =  - 0.011, p = 0.930) (r = 0.092, p = 0.466) respectively. Linear regression analysis demonstrated that TERF1 was significantly associated with functional disability (B = 0.771, p = 0.025). Mediation analysis indicated that TERF1 was not significantly associated with disease activity (B = 5.764, p = 0.326), while disease activity was significantly associated with functional disability (B = 0.019, p = 0.0069), and the indirect effect was not statistically significant (bootstrap 95% confidence interval, - 0.066 to 0.363).
CONCLUSIONS: TERT and TERF2 were significantly associated with RA susceptibility, whereas TERF1 may influence functional impairment through mechanisms independent of inflammatory disease activity. These findings highlight the potential role of telomere-associated proteins in the pathogenesis and clinical heterogeneity of RA. Key Points • Telomerase reverse transcriptase (TERT) and telomeric repeat-binding factor 2 (TERF2) were associated with rheumatoid arthritis susceptibility. • Telomeric repeat-binding factor 1 (TERF1) was identified as a predictor of functional impairment in rheumatoid arthritis. • Functional disability may be influenced by inflammation-independent mechanisms rather than disease activity alone. • Telomere regulatory pathways may contribute to both disease development and progression in rheumatoid arthritis.