EPIGENETIC BIOMARKERS FOR PREDICTING PROGRESSION OF AUTOIMMUNE DISEASES: A MULTI-COHORT LONGITUDINAL INTEGRATIVE ANALYSIS OF DNA METHYLATION, MICRORNA SIGNATURES, AND EPIGENETIC AGE

Abstract

Background: Autoimmune diseases show heterogeneous diseases courses with mainly stable low activity or rapid disease course with irreversible organ damage. Conventional clinical and serologic measures are often behind the biological change. Epigenetic marks - especially DNA methylation, non-coding RNAs and epigenetic age acceleration - combine genetic risk and immune activation and may be predictive of progression earlier and in a quantitative way. Methods: We conducted a retrospective retrospective longitudinal integrative analysis of 5 publicly available cohorts of patients with autoimmune conditions (systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], Crohn's disease [CD] and relapsing-remitting multiple sclerosis [RRMS], and islet autoimmunity progressing to type 1 diabetes [T1D]). Harmonization of genome wide DNA methylation analysis (Illumina 450K/EPIC) with the use of standard contained preprocessing/ batch correction and leukocyte deconvolution was performed. Candidate epigenetic features were taken from interferon pathway CpGs, MHC region differentially methylated loci and progression-endorsed loci from autoimmune EWAS. Constructed characteristics of the circulating microRNA-features (if available) were merged as immune cell enriched signatures. Epigenetic age was determined with a Horvath clock and was expressed as age acceleration. Disease progression endpoints were predefined within each cohort (e.g. flare persistence/remission in SLE; radiographic progression in RA; stricturing/penetrating complications in CD; disability worsening/conversion phenotype in MS; progression of islet autoimmunity to clinical T1D). Predictive ability was measured using cross-validated elastic-net and Cox regression. Results: A parsimonious epigenetic panel enriched for interferon-related hypomethylation, MHC-linked methylation variation and epigenetic age acceleration was predictive of progression with pooled AUC of 0.81 (95% CI (0.78 - 0.84) versus baseline clinical covariates alone (AUC of 0.69, 95% CI (0.66 - 0.72)). In terms of time- to event, high risk epigenetic scores were found to be associated with faster progression (pooled HR 2.14, 95% CI 1.72-2.67). Integration of microRNA immun enrichment features enhanced discrimination in MS and IBD subsets. Conclusion: Cross-disease epigenetic signatures offer early, scalable risk stratification for autoimmune progression and are consistent with a convergent biology characterized by interferon signaling, changes in immune-cell composition, and rapid biological aging.