POS1480-HPR EXPLORING THE CAUSAL RELATIONSHIP BETWEEN AGING AND AUTOIMMUNE DISEASES: A BIDIRECTIONAL MENDELIAN RANDOMIZATION STUDY

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Background: Autoimmune diseases (ADs) arise from the immune system's inappropriate responses against the body's own tissues, leading to a breakdown of immune tolerance. Like other complex diseases, ADs often take years to develop, with aging (AG) playing a significant role in altering immune function and contributing to their onset. Moreover, ADs not only emerge as a consequence of aging-related immune dysfunction but can also accelerate pathological aging. While observational studies have identified an association between AG and ADs, the causal relationship between the two remains unclear. Objectives: This study aimed to evaluate the potential causal relationship between AGs and ADs using latent heritable confounder Mendelian randomization (LHC-MR) analysis, which accounts for confounding effects and sample overlap. Methods: The latest and most comprehensive European pooled genome-wide association study (GWAS) data were used to explore the causal relationship between AGs and ADs. The pooled GWAS data related to AGs came from large-scale meta-analyses, covering 12 major traits, divided into: epigenetic clock-related indicators (DNA methylation GrimAge acceleration, DNA methylation Hannum age acceleration, intrinsic epigenetic age acceleration, and DNA methylation PhenoAge acceleration); lifespan-related indicators (lifespan, healthspan, longevity, and healthy aging); cellular aging-related indicators (leukocyte telomere length [LTL] and mitochondrial DNA); and other markers, such as frailty index (FI) and facial aging. Similarly, we selected six major ADs from large meta-analyses for higher statistical power and clinical relevance, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), Crohn's disease (CD), ulcerative colitis (UC), and primary sclerosing cholangitis (PSC). To evaluate the causal relationship between AGs and ADs, we used the LHC-MR approach. This advanced approach extends the standard MR model to improve the reliability and precision of causal effect estimates by taking into account potential sample overlap and genetic confounders that may affect the exposure-outcome relationship. A unidirectional relationship is defined as a P value in one direction below the Bonferroni correction threshold (0.05/72/2=3.47×10-4) and P > 0.05 in the other direction, while P < 3.47×10 −4 in both directions indicates a bidirectional causal relationship. Results: We identified two significant negative causal relationships in the forward analysis of AG and ADs. Specifically, higher GrimAge was associated with a reduced risk of RA (OR: 0.726; 95% CI: 0.619–0.850), while an increase in healthy lifespan was linked to a lower risk of UC (OR: 0.368; 95% CI: 0.356–0.380). In contrast, two significant positive causal relationships were observed: elevated LTL was associated with an increased risk of PSC (OR: 1.88; 95% CI: 1.435–2.469) and SLE (OR: 2.626; 95% CI: 2.498–2.761) (Figure 1a). These findings may be explained by the role of telomere dynamics in immune system function; the loss of telomeric sequences at chromosome ends contributes to cell cycle arrest, T-cell apoptosis, and immunosenescence, ultimately weakening the adaptive immune response. The reverse analysis revealed six significant positive causal relationships. Notably, increased FI was associated with a higher risk of RA (OR: 1.167; 95% CI: 1.110–1.227), T1D (OR: 1.241; 95% CI: 1.123–1.370), and UC (OR: 1.143; 95% CI: 1.072–1.218). In contrast, three significant negative causal relationships were identified, with the most prominent being SLE, which was associated with a shortened Health aging (OR: 0.948; 95% CI: 0.932–0.964) (Figure 1b). Notably, bidirectional causality was observed only in three trait pairs: lifespan-T1D, LTL-CD, and LTL-T1D. Conclusion: In conclusion, we found using the LHC-MR method that an increase in AGs seems to reduce the occurrence of ADs, whereas an increase in LTL seems to cause the occurrence of ADs. At the same time, the occurrence of ADs can lead to aging processes, such as the occurrence of FI and the reduction of shortened Health aging. However, the causal relationship among the remaining AGs-ADs remains unclear, and the underlying mechanisms require further investigation. These results reveal a complex interplay between AGs and ADs and provide a basis for the design of future interventions. REFERENCES: [1] Zheng, Y., Liu, Q., Goronzy, J. J. & Weyand, C. M. Immune aging - A mechanism in autoimmune disease. Semin Immunol.2023; 69: 101814. [2] Chen, L., Wu, B., Mo, L. et al. Associations between biological ageing and the risk of, genetic susceptibility to, and life expectancy associated with rheumatoid arthritis: a secondary analysis of two observational studies. Lancet Healthy Longev.2024; 5: e45-e55. Acknowledgements: NIL . Disclosure of Interests: None declared . © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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