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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Qishun Geng1,2
  • Chaoying Wen3,4
  • Meijia Yang2
  • Yuhan Zhou5
  • Meng Yang6
  • Qishun Geng1,2
  • Jie Zhao1,2
6 affiliations
  1. 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  2. 2Internet Medical and System Applications of National Engineering Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  3. 3China-Japan Friendship Clinical Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  4. 4Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
  5. 5Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  6. 6Department of Orthopedics, Henan Provincial Third People’s Hospital, Zhengzhou, Henan, China
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Abstract

Purpose: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

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Cite

BibTeXRIS
BibTeX
@article{geng2026integrative,
  title = {{Integrative population genetics and multi-omics reveal IL15RA as a shared pathogenic hub in rheumatoid arthritis-related heart failure}},
  author = {Qishun Geng and Chaoying Wen and Meijia Yang and Yuhan Zhou and Meng Yang and Qishun Geng and Jie Zhao},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1956897},
  url = {https://doi.org/10.3389/fimmu.2026.1956897},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Integrative population genetics and multi-omics reveal IL15RA as a shared pathogenic hub in rheumatoid arthritis-related heart failure
AU  - Qishun Geng
AU  - Chaoying Wen
AU  - Meijia Yang
AU  - Yuhan Zhou
AU  - Meng Yang
AU  - Qishun Geng
AU  - Jie Zhao
PY  - 2026
DA  - 2026/10/12
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1956897
UR  - https://doi.org/10.3389/fimmu.2026.1956897
AB  - Purpose: 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.  Methods: 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).  Results: 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.  Conclusion: 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.
SN  - 1664-3224
ER  -