Lu Jiawen, Wang Zhenqian, Zhang Jiaying, Jiao Feng, Zou Chenfeng, Han Liyuan, Jiang Guozhi
School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China; School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangzhou Centre for Applied Mathematics, Guangzhou University, Guangzhou, Guangdong, China.
J Lipid Res. 2024 Apr;65(4):100528. doi: 10.1016/j.jlr.2024.100528. Epub 2024 Mar 6.
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], P 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], P 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.
长期以来，血脂异常一直被认为会增加死亡风险；然而，血脂特征与死亡率之间的确切关联仍不明确。我们的研究旨在探讨血脂特征对全因死亡率和特定病因死亡率的因果效应。在英国生物银行的407,951名欧洲参与者队列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）分析。纳入了六个血脂特征，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)，以研究与死亡率的因果关联。进行两样本MR分析以重复每种血脂特征与全因死亡率之间的关联。单变量MR结果显示，基因预测的较高ApoA1与全因死亡风险降低显著相关（HR[95%CI]：0.93[0.89 - 0.97]，P值 = 0.001），这在两样本MR分析中得到了验证。较高的脂蛋白(a)与全因死亡风险增加相关（1.03[1.01 - 1.04]，P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效应。同时，非线性MR未发现血脂与全因死亡率之间存在非线性的证据。我们对特定病因死亡率的研究表明，ApoA1与癌症死亡率之间存在提示性的负相关，脂蛋白(a)与心血管疾病死亡率之间存在显著正相关，脂蛋白(a)与消化系统疾病死亡率之间存在提示性正相关。高LDL-C与心血管疾病死亡率风险增加相关，但与神经退行性疾病死亡率风险降低相关。研究结果表明，实施提高ApoA1和降低脂蛋白(a)水平的干预措施可能会改善整体健康状况，并降低癌症和消化系统疾病的死亡率。
