Integrative population genetics and multi-omics reveal IL15RA as a shared pathogenic hub in rheumatoid arthritis-related heart failure

Abstract

Rheumatoid arthritis (RA) patients face a significantly elevated risk of heart failure (HF), but population-level evidence and underlying mechanisms remain unclear. We aimed to assess the RA-HF association using national data and identify dietary compounds targeting shared inflammatory pathways. We analyzed NHANES data (n=2,931) and performed two-sample Mendelian randomization (MR). Integrated machine learning, single-cell transcriptomics, clinical samples, and in vitro experiments identified therapeutic targets and evaluated the effectiveness of dioscin (a yam-derived saponin). The rate of HF in RA patients is high, and RA patients with HF have a worse prognosis. MR analysis also revealed that RA was a significant HF risk factor. IL15RA emerged as a shared causal target, whose silencing suppressed TNF-α-induced ICAM-1 in endothelial cells and reduced M1 (CD86 + ) macrophage polarization. Mechanistically, MIF signaling were strongly implicated in the crosstalk between endothelial cells and macrophages. Dioscin bound IL15RA and reduced its expression in both cell types, phenocopying IL15RA silencing. This study identifies IL15RA as a key therapeutic target linking RA and HF, and dioscin as a dietary phytochemical with anti-inflammatory potential. Our findings provide a population-based framework and a readily translatable nutritional strategy for mitigating cardiac comorbidity in RA patients.