Mendelian Randomization and Bioinformatics Identify IFI27 as a Candidate Biomarker for Recurrent Pregnancy Loss in...

Systemic lupus erythematosus (SLE) is associated with adverse pregnancy outcomes, but its causal relationship with recurrent pregnancy loss (RPL) and their shared molecular characteristics remain unclear. This study integrated bidirectional two-sample Mendelian randomization (MR) and transcriptomic bioinformatics analyses to investigate this relationship and identify candidate shared biomarkers. FinnGen and UK Biobank were selected because they provide large, non-overlapping, European-ancestry genome-wide association study (GWAS) summary statistics. Differentially expressed genes (DEGs) were identified from GSE61635 (blood; |log₂ fold change| > 1) and GSE165004 (endometrium; |log₂ fold change| > 0.5) using an adjusted P < 0.05, followed by functional enrichment, protein-protein interaction (PPI) analysis, hub-gene screening, least absolute shrinkage and selection operator (LASSO) regression, external validation using GSE50772 and GSE198700, receiver operating characteristic (ROC) analysis, and single-sample gene set enrichment analysis (ssGSEA). Genetically predicted SLE was associated with a statistically significant but quantitatively modest increase in spontaneous miscarriages (inverse-variance weighted [IVW] odds ratio [OR] = 1.01, 95% confidence interval [CI] = 1.00-1.02; P < 0.001). Instrument strength was adequate, and sensitivity analyses detected no material heterogeneity, directional pleiotropy, or influential single variant. Fifty-nine shared DEGs were enriched in antiviral immune responses, cell adhesion, and apoptosis-related processes. IFI27 was consistently overexpressed in SLE blood but underexpressed in RPL endometrium and chorionic villi, whereas CXCL11 lacked consistent external validation. Retrospective ROC analyses yielded areas under the curve (AUCs) of 0.822 for SLE and 0.872 for RPL. Computationally inferred ssGSEA scores showed correlations between IFI27 expression and several immune-cell signatures, including T helper 2 (Th2) cells. These findings identify IFI27 as a candidate biomarker shared by SLE and RPL; however, prospective clinical and experimental studies are required to validate its biological and clinical significance.