4.7 Article

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis

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

  1. Academy of Finland [297338, 307247, 322098, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
  2. Novo Nordisk foundation [NNF17OC0027034, NNF17OC0026062]
  3. Social Insurance Institution of Finland
  4. Competitive State Research Financing of the Expert Responsibility area of Kuopio
  5. ERDF European Regional Development Fund [539/2010: A31592]
  6. EU Horizon 2020 [633595, 755320]
  7. EU Research Council [742927]
  8. Sigrid Juselius
  9. Finnish Cardiovascular Research
  10. Juho Vainio
  11. Paavo Nurmi
  12. Finnish Cultural
  13. Tampere Tuberculosis
  14. Emil Aaltonen
  15. YrjoJahnsson
  16. Signe and Ane Gyllenberg
  17. Finnish Diabetes Research
  18. British Heart Foundation Intermediate Clinical Research Fellowship [FS/18/23/33512]
  19. National Institute for Health Research Oxford Biomedical Research Centre
  20. Oulu Health andWellfare Center
  21. Academy of Finland (AKA) [307247, 297338, 307247, 297338] Funding Source: Academy of Finland (AKA)

向作者/读者索取更多资源

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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