期刊
EUROPEAN HEART JOURNAL
卷 42, 期 12, 页码 1160-1169出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehaa972
关键词
ANGPTL3; ANGPTL4; LPL; Lipoprotein lipids; Lipoprotein subclasses; Amino acids; Glycoprotein acetyls; Mendelian randomization; Drug targets
资金
- Academy of Finland [297338, 307247, 322098, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
- Novo Nordisk foundation [NNF17OC0027034, NNF17OC0026062]
- Social Insurance Institution of Finland
- Competitive State Research Financing of the Expert Responsibility area of Kuopio
- ERDF European Regional Development Fund [539/2010: A31592]
- EU Horizon 2020 [633595, 755320]
- EU Research Council [742927]
- Sigrid Juselius
- Finnish Cardiovascular Research
- Juho Vainio
- Paavo Nurmi
- Finnish Cultural
- Tampere Tuberculosis
- Emil Aaltonen
- YrjoJahnsson
- Signe and Ane Gyllenberg
- Finnish Diabetes Research
- British Heart Foundation Intermediate Clinical Research Fellowship [FS/18/23/33512]
- National Institute for Health Research Oxford Biomedical Research Centre
- Oulu Health andWellfare Center
- Academy of Finland (AKA) [307247, 297338, 307247, 297338] Funding Source: Academy of Finland (AKA)
The study found that genetic mimicry of ANGPTL4 inhibition and LPL enhancement have similar metabolic effects, while genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Inhibition of ANGPTL4 and enhancement of LPL through genetic mimicry were associated with a lower risk of coronary heart disease and type 2 diabetes.
Aims 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. Methods and results 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. Conclusions 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.
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