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While crudely quantified lipoproteins have been reported to affect the risk of breast cancer, the effects of subclass lipoproteins characterized by particle size, particle number, and lipidomes remain unknown. Utilizing nuclear magnetic resonance-based GWAS of 85 lipoprotein traits, we performed two-sample univariable Mendelian randomization (MR) to evaluate the causal relationship between each trait with breast cancer (Ncase/control = 133,384/113,789) and with its estrogen receptor (ER) subtypes. Then, we applied multivariable MR to investigate the independent effects considering both general and central obesity. In univariable MR, a heterogeneous effect of subclass high-density lipoproteins (HDL) was observed, in which small HDL traits (ORs ranged from 0.89 to 0.94) were associated with a decreased risk of breast cancer while non-small HDLs traits (OR ranged from 1.04 to 1.08) were associated with an increased risk of breast cancer. Very-low-density lipoproteins (VLDL) traits and serum total triglycerides (TG) were associated with a decreased risk of breast cancer (ORs ranged from 0.88 to 0.94). Similar association patterns were found for ER + subtype. In multivariable MR, only the protective effects of small HDL, VLDL and TG on ER + subtype remained significant. We identified a heterogeneous effect of subclass HDLs and a consistent protective effect of VLDL on breast cancer. Only the effects of small HDL and VLDL on ER + subtype remained robust after controlling for obesity. These findings provide new insight into the causal pathway underlying lipoproteins and breast cancer. © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.


Jinyu Xiao, Yu Hao, Xueyao Wu, Xunying Zhao, Bin Xu, Chenghan Xiao, Wenqiang Zhang, Li Zhang, Huijie Cui, Chao Yang, Peijing Yan, Mingshuang Tang, Yutong Wang, Lin Chen, Yunjie Liu, Yanqiu Zou, Chunxia Yang, Yuqin Yao, Jiayuan Li, Xia Jiang, Ben Zhang. Nuclear magnetic resonance-determined lipoprotein profile and risk of breast cancer: a Mendelian randomization study. Breast cancer research and treatment. 2023 Jul;200(1):115-126

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PMID: 37162625

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