IFI44L promoter hypomethylation as an epigenetic biomarker of systemic lupus erythematosus: A systematic review and meta-analysis

Background Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease characterized by dysregulated type I interferon signaling. Epigenetic alterations, particularly DNA methylation changes in interferon-regulated genes, have emerged as promising biomarkers for disease diagnosis and stratification. Among these, IFI44L promoter hypomethylation has been repeatedly reported as one of the most consistent and disease specific in SLE. Objective To systematically evaluate the evidence on IFI44L promoter methylation in SLE and to quantitatively synthesize its epigenetic and diagnostic performance across diverse populations using meta-analytic approaches. Methods A systematic search of published literature was conducted to identify studies reporting IFI44L promoter methylation in patients with SLE and controls. Study characteristics, ethnicity, cell type, direction of methylation, CpG hypo/hyper methylation counts were extracted. Descriptive analyses were performed across ethnicities and cell types. Diagnostic performance was summarized as the pooled area under the receiver operating characteristic (ROC) curve (AUC). Variance of AUC estimates was approximated using the Hanley-McNeil method, and a random-effects meta-analysis (DerSimonian–Laird) was applied to account for between-study heterogeneity. Results 16 study datasets reporting hypomethylation of the IFI44L promoter were included. IFI44L promoter hypomethylation was consistently observed across ethnic groups and biological sample types. Descriptive subgroup analyses identified heterogeneity in the magnitude of IFI44L promoter hypomethylation across ethnic groups, study periods, and methylation profiling methodologies, whereas differences according to biological sample type were less pronounced and did not reach statistical significance. Hypomethylation predominated over hypermethylation among studies reporting both methylation directions. Diagnostic AUC values varied across studies but were largely independent of sample size and the magnitude of hypomethylation. The pooled area under the curve (AUC) was 0.74 (95% CI 0.64–0.84), indicating moderate overall diagnostic performance. Conclusion IFI44L promoter hypomethylation represents a significant and reproducible epigenetic signature of SLE across populations and study designs. Despite variability in methylation magnitude, its diagnostic performance remains consistent, supporting IFI44L methylation as a promising biomarker for SLE.