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Causal plasma metabolites for breast cancer risk: a two-sample Mendelian randomization study with colocalization
Hanghang Chen1, Yueyuan Xu2, Zepeng Wang3,4
1Breast Surgery, The First Affiliated Hospital of Henan University of Chinese Medicine, No.19 Renmin Road, Zhengzhou, 450000, Henan Province, China. hanghang461@hactcm.edu.cn.
Background:
Breast cancer pathogenesis involves complex metabolic dysregulation, yet causal biomarkers remain elusive. This study aimed to assess causal effects of 1,400 human plasma metabolites on breast cancer (BC) risk using a two-sample Mendelian randomization (MR) framework.
Methods:
We employed a rigorous two-sample Mendelian randomization framework with tiered quality control (Bonferroni correction, sensitivity analyses, meta-analyses) to investigate causal metabolite-BC associations. Colocalization (PPH4 > 0.80) and phenome-wide MR (2,099 FinnGen phenotypes) validated mechanistic specificity and clinical safety profiles.
Results:
Five genetically determined plasma metabolites were identified as the potential causal biomarkers for BC risk: 3,5-dichloro-2,6-dihydroxybenzoic acid (odds ratio [OR]: 0.90; 95% confidence interval [CI] 0.87-0.94; p < 0.001), carnitine C14 (OR: 0.72; 95% CI 0.64-0.83; p < 0.001) and epiandrosterone sulfate (OR: 1.04; 95% CI 1.01-1.06; p < 0.001), Glyco-beta-muricholate (OR: 0.95; 95% CI 0.93-0.97; p < 0.001), N4-acetylcytidine (OR: 0.93; 95% CI 0.91-0.96; p < 0.001). Colocalization analysis showed strong evidence for Glyco - beta - muricholate and Epiandrosterone sulfate with BC risk (PPH4 = 1). PheWAS-MR revealed metabolite-specific safety profiles, with carnitine C14 showing broadest phenotypic associations (96 outcomes).
Conclusions:
This study establishes carnitine C14 as a novel protective biomarker and epiandrosterone sulfate as a risk biomarker for breast cancer, with colocalization evidence supporting their therapeutic targeting. The metabolic risk profile provides a foundation for precision prevention strategies.
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