Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization

Abstract Objective To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA. Methods Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association. Results In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association. Conclusion Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.