目的:本研究旨在使用双样本孟德尔随机(TSMR)方法和贝叶斯模型平均孟德尔随机(BMA-MR)方法来研究特定脂质与乳腺癌(BC)风险之间的关系。
方法:该研究分析了来自179个脂质粒的大规模GWAS数据集的数据,以评估不同分子亚型中脂质粒与BC风险之间的关系。TSMR被用来探索因果关系,同时进行BMA-MR方法以验证结果。这项研究通过Cochran的Q评估了异质性和水平多效性,MR-Egger截距测试,MR-PRESSO此外,我们进行了留一法敏感性分析,以评估个体单核苷酸多态性对MR研究的影响.
结果:通过检查179个脂质组特征作为暴露,BC作为结果,这项研究揭示了甘油磷脂的显著因果效应,鞘脂,和甘油脂对BC的风险。具体来说,对于雌激素受体阳性BC(ER+BC),磷脂酰胆碱(P<0.05)和磷脂酰肌醇(OR:0.916-0.966,P<0.05)在甘油磷脂中发挥显著作用,随着甘油酯的重要性(二酰基甘油(OR=0.923,P<0.001)和三酰基甘油,OR:0.894-0.960,P<0.05))。然而,本研究未观察到鞘脂对ER+BC的显著影响.在雌激素受体阴性BC(ER-BC)的情况下,不仅仅是甘油磷脂,鞘脂(OR=1.085,P=0.008),和甘油脂(OR=0.909,P=0.002)产生了影响,但也发现了甾醇的保护作用(OR:1.034-1.056,P<0.05)。在ER-BC中,甘油脂的突出度最小。磷脂酰乙醇胺(OR:1.091-1.119,P<0.05)是ER-BC的重要因果效应。
结论:研究结果表明,磷脂酰肌醇和甘油三酯水平降低了BC的风险,表明这些脂质分子具有潜在的保护作用。此外,这项研究阐明了BC复杂的脂质代谢途径,突出显示不同的脂质组结构变异,这些变异可能在不同的分子亚型中产生不同的影响。
OBJECTIVE: This
study aims to investigate the association between specific lipidomes and the risk of breast cancer (BC) using the Two-Sample Mendelian Randomization (TSMR) approach and Bayesian Model Averaging Mendelian Randomization (BMA-MR) method.
METHODS: The
study analyzed data from large-scale GWAS datasets of 179 lipidomes to assess the relationship between lipidomes and BC risk across different molecular subtypes. TSMR was employed to explore causal relationships, while the BMA-MR method was carried out to validate the results. The
study assessed heterogeneity and horizontal pleiotropy through Cochran\'s Q, MR-Egger intercept tests, and MR-PRESSO. Moreover, a leave-one-out sensitivity analysis was performed to evaluate the impact of individual single nucleotide polymorphisms on the MR study.
RESULTS: By examining 179 lipidome traits as exposures and BC as the outcome, the study revealed significant causal effects of glycerophospholipids, sphingolipids, and glycerolipids on BC risk. Specifically, for estrogen receptor-positive BC (ER+ BC), phosphatidylcholine (P < 0.05) and phosphatidylinositol (OR: 0.916-0.966, P < 0.05) within glycerophospholipids play significant roles, along with the importance of glycerolipids (diacylglycerol (OR = 0.923, P < 0.001) and triacylglycerol, OR: 0.894-0.960, P < 0.05)). However, the
study did not observe a noteworthy impact of sphingolipids on ER+BC. In the case of estrogen receptor-negative BC (ER- BC), not only glycerophospholipids, sphingolipids (OR = 1.085, P = 0.008), and glycerolipids (OR = 0.909, P = 0.002) exerted an influence, but the protective effect of sterols (OR: 1.034-1.056, P < 0.05) was also discovered. The prominence of glycerolipids was minimal in ER-BC. Phosphatidylethanolamine (OR: 1.091-1.119, P < 0.05) was an important causal effect in ER-BC.
CONCLUSIONS: The findings reveal that phosphatidylinositol and triglycerides levels decreased the risk of BC, indicating a potential protective role of these lipid molecules. Moreover, the
study elucidates BC\'s intricate lipid metabolic pathways, highlighting diverse lipidome structural variations that may have varying effects in different molecular subtypes.