Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.
Eur Heart J. 2021 Mar 21;42(12):1160-1169. doi: 10.1093/eurheartj/ehaa972.
Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.
Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.
Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.
血管生成素样蛋白 3（ANGPTL3）和 4（ANGPTL4）抑制脂蛋白脂肪酶（LPL），是降低循环甘油三酯和降低心血管风险的新兴药物靶点。本研究旨在探讨基因模拟 ANGPTL3 和 ANGPTL4 抑制与基因模拟 LPL 增强的分子作用，并对其进行比较。
在六个队列中，对多达 61240 名参与者的广泛血清脂质和代谢产物谱（208 项指标）进行了 ANGPTL3（rs11207977-T）、ANGPTL4（rs116843064-A）和 LPL（rs115849089-A）遗传变异与人体测量指标、葡萄糖-胰岛素代谢、血压、肾功能标志物和心脏代谢终点之间的关联进行了特征描述。还通过全基因组汇总数据探讨了这些遗传变异与 ANGPTL3 rs11207977-T 的关联。ANGPTL4 rs116843064-A 和 LPL rs115849089-A 在脂蛋白和脂质指标上表现出惊人相似的关联模式。然而，与 ANGPTL3 rs11207977-T 相对应的关联则不同，包括 LDL 和高密度脂蛋白颗粒浓度和组成。三种基因型均与炎症生物标志物糖蛋白乙酰基浓度降低以及 ANGPTL3 抑制和 LPL 增强的基因模拟有关，同时也与 CRP 降低有关。ANGPTL4 抑制和 LPL 增强的基因模拟与较低的腰臀比、改善的胰岛素-葡萄糖代谢以及较低的冠心病和 2 型糖尿病风险相关，而 ANGPTL3 抑制的基因模拟与改善的肾功能相关。
ANGPTL4 抑制和 LPL 增强的基因模拟具有非常相似的全身代谢作用，而 ANGPTL3 抑制的基因模拟则表现出不同的代谢作用，这表明可能涉及与 LPL 无关的途径。ANGPTL4 抑制和 LPL 增强的基因模拟与冠心病和 2 型糖尿病的风险降低相关。这些发现进一步证明了通过药理学方法直接或通过上游作用增强 LPL 活性可能对人类健康有益。
