Genetic-multi-omics causal inference coupled with integrative in-vitro toxicology reveals immune-metabolite mediators for aortic aneurysm risk
- 1epartment of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
Abstract
ObjectiveAortic aneurysm (AA) is a life-threatening vascular disease characterized by immune disturbance and metabolic dysregulation. Multi-omics-driven precision toxicity prediction, integrating human genetic causal inference with functional in-vitro toxicology, remains under-explored for uncovering metabolite mediators underlying AA disease risk.This study aimed to dissect metabolite-dependent causal pathways linking immune cells to AA, and evaluate dose-response cytotoxicity of key mediating metabolites toward vascular cells.MethodsTwo-sample Mendelian randomization (MR) and two-step mediation analysis were performed using European-ancestry GWAS summary datasets covering 731 immune-cell traits, 1,091 plasma metabolites, 3,230 AA cases and 475,964 controls. Complementary in-vitro CCK-8 cytotoxicity experiments on human aortic smooth muscle cells (HASMCs) were further conducted for candidate metabolites Adrenate (22:4n6) and BAFF-R.ResultsBAFF-R on CD20− (OR = 0.859, 95%CI: 0.797–0.926, P = 7.17 × 10−5) and, to a lesser extent, Granulocyte AC (OR = 0.900, 95%CI: 0.843–0.961, P = 1.57 × 10−3) emerged as candidate protective immune-cell markers for AA. Adrenate (22:4n6) and Nisinate (24:6n3) mediated 4.47% and 9.84% of these protective effects, respectively. Adrenate triggered significant dose-dependent cytotoxicity in HASMCs.ConclusionThis multi-omics genetic-toxicology study provides causal genetic evidence for immune-metabolite regulatory axes in AA pathogenesis. Notably, Adrenate presents dual biological effects: it transmits immune-protective signals but exerts direct vascular cellular toxicity. Our findings highlight the utility of MR-assisted precision toxicity prediction for disease risk evaluation and therapeutic target mining for AA.
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BibTeX
@article{li2026geneticmultiomics,
title = {{Genetic-multi-omics causal inference coupled with integrative in-vitro toxicology reveals immune-metabolite mediators for aortic aneurysm risk}},
author = {Jia Li and Bolin Wang and Yuming Hao and Shipan Wang and Xiaonan Li and Fan Zhang and Sichong Qian and Haiyang Li},
journal = {Frontiers in Genetics},
year = {2026},
month = nov,
doi = {10.3389/fgene.2026.2010274},
url = {https://doi.org/10.3389/fgene.2026.2010274},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic-multi-omics causal inference coupled with integrative in-vitro toxicology reveals immune-metabolite mediators for aortic aneurysm risk
AU - Jia Li
AU - Bolin Wang
AU - Yuming Hao
AU - Shipan Wang
AU - Xiaonan Li
AU - Fan Zhang
AU - Sichong Qian
AU - Haiyang Li
PY - 2026
DA - 2026/11/03
JO - Frontiers in Genetics
DO - 10.3389/fgene.2026.2010274
UR - https://doi.org/10.3389/fgene.2026.2010274
AB - ObjectiveAortic aneurysm (AA) is a life-threatening vascular disease characterized by immune disturbance and metabolic dysregulation. Multi-omics-driven precision toxicity prediction, integrating human genetic causal inference with functional in-vitro toxicology, remains under-explored for uncovering metabolite mediators underlying AA disease risk.This study aimed to dissect metabolite-dependent causal pathways linking immune cells to AA, and evaluate dose-response cytotoxicity of key mediating metabolites toward vascular cells.MethodsTwo-sample Mendelian randomization (MR) and two-step mediation analysis were performed using European-ancestry GWAS summary datasets covering 731 immune-cell traits, 1,091 plasma metabolites, 3,230 AA cases and 475,964 controls. Complementary in-vitro CCK-8 cytotoxicity experiments on human aortic smooth muscle cells (HASMCs) were further conducted for candidate metabolites Adrenate (22:4n6) and BAFF-R.ResultsBAFF-R on CD20− (OR = 0.859, 95%CI: 0.797–0.926, P = 7.17 × 10−5) and, to a lesser extent, Granulocyte AC (OR = 0.900, 95%CI: 0.843–0.961, P = 1.57 × 10−3) emerged as candidate protective immune-cell markers for AA. Adrenate (22:4n6) and Nisinate (24:6n3) mediated 4.47% and 9.84% of these protective effects, respectively. Adrenate triggered significant dose-dependent cytotoxicity in HASMCs.ConclusionThis multi-omics genetic-toxicology study provides causal genetic evidence for immune-metabolite regulatory axes in AA pathogenesis. Notably, Adrenate presents dual biological effects: it transmits immune-protective signals but exerts direct vascular cellular toxicity. Our findings highlight the utility of MR-assisted precision toxicity prediction for disease risk evaluation and therapeutic target mining for AA.
SN - 1664-8021
ER -