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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