Dyslipidemia has long been implicated in elevating mortality risk; yet, the precise associations between lipid traits and mortality remained undisclosed. Our study aimed to explore the causal effects of lipid traits on both all-cause and cause-specific mortality. One-sample Mendelian randomization (MR) with linear and nonlinear assumptions was conducted in a cohort of 407,951 European participants from the UK Biobank. Six lipid traits, consisting of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein(a), were included to investigate the causal associations with mortality. Two-sample MR was performed to replicate the association between each lipid trait and all-cause mortality. Univariable MR results showed that genetically predicted higher ApoA1 was significantly associated with a decreased all-cause mortality risk (HR[95% CI]:0.93 [0.89–0.97], value = 0.001), which was validated by the two-sample MR analysis. Higher lipoprotein(a) was associated with an increased risk of all-cause mortality (1.03 [1.01–1.04], value = 0.002). Multivariable MR confirmed the direct causal effects of ApoA1 and lipoprotein(a) on all-cause mortality. Meanwhile, nonlinear MR found no evidence for nonlinearity between lipids and all-cause mortality. Our examination into cause-specific mortality revealed a suggestive inverse association between ApoA1 and cancer mortality, a significant positive association between lipoprotein(a) and cardiovascular disease mortality, and a suggestive positive association between lipoprotein(a) and digestive disease mortality. High LDL-C was associated with an increased risk of cardiovascular disease mortality but a decreased risk of neurodegenerative disease mortality. The findings suggest that implementing interventions to raise ApoA1 and decrease lipoprotein(a) levels may improve overall health outcomes and mitigate cancer and digestive disease mortality.

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血脂与全因和特定原因死亡风险的因果关系：孟德尔随机研究

长期以来，血脂异常一直被认为与死亡风险升高有关。然而，血脂特征与死亡率之间的确切关系仍未公开。我们的研究旨在探讨脂质特征对全因和特定原因死亡率的因果影响。在来自英国生物银行的 407,951 名欧洲参与者中进行了具有线性和非线性假设的单样本孟德尔随机化 (MR)。包括六种脂质特征，包括低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、甘油三酯、载脂蛋白A1（ApoA1）、载脂蛋白B（ApoB）和脂蛋白（a）调查与死亡率的因果关系。进行两个样本的 MR 来复制每个脂质特征与全因死亡率之间的关联。单变量 MR 结果显示，基因预测较高的 ApoA1 与全因死亡风险降低显着相关（HR[95% CI]：0.93 [0.89–0.97]，值 = 0.001），这通过两样本 MR 分析得到验证。较高的脂蛋白(a) 与全因死亡风险增加相关（1.03 [1.01–1.04]，值 = 0.002）。多变量 MR 证实了 ApoA1 和脂蛋白 (a) 对全因死亡率的直接因果影响。与此同时，非线性磁共振没有发现血脂与全因死亡率之间存在非线性的证据。我们对特定原因死亡率的检查显示，ApoA1 与癌症死亡率之间存在暗示性负相关，脂蛋白 (a) 与心血管疾病死亡率之间存在显着正相关，脂蛋白 (a) 与消化系统疾病死亡率之间存在暗示性正相关。高 LDL-C 与心血管疾病死亡风险增加相关，但与神经退行性疾病死亡风险降低相关。研究结果表明，实施干预措施来提高 ApoA1 和降低脂蛋白 (a) 水平可以改善整体健康状况并降低癌症和消化系统疾病的死亡率。