Heterozygous carrier status for ANGPTL3 loss-of-function mutations was associated with a 34% reduction in odds of coronary artery disease (OR 0.66; 95% CI 0.44 to 0.98; p=0.04).
Observational (n=184,911)
Does ANGPTL3 deficiency reduce the risk of coronary artery disease?
ANGPTL3 deficiency, whether genetic or measured by circulating biomarkers, is associated with a significantly reduced risk of coronary artery disease and myocardial infarction.
Odds Ratio: 0.66 (95% CI 0.44–0.98)
p-value: p=0.04
BACKGROUND Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES The study goal was to leverage 3 distinct lines of evidence – a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in myocardial infarction (MI) patients – to test if ANGPTL3 deficiency is associated with lower risk for CAD. METHODS We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 individuals with CAD and 158,200 controls. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 individuals presenting with MI and 3,232 controls. RESULTS The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 individuals was a heterozygous carrier for an LOF mutation. Compared to those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS ANGPTL3 deficiency is associated with protection from CAD.
“The family members with complete loss of ANGPTL3 have extraordinarily low cholesterol. The interesting thing about this family is the individuals with total loss of this gene had siblings with normal copies of the same gene. So we could compare people with differences in the function of this gene who are otherwise closely related genetically and share similar environments. It's an anecdotal study of one family, but we felt it might provide some insight into the effects of blocking ANGPTL3.”
Stitziel et al. (Sat,) conducted a observational in Coronary artery disease (n=184,911). ANGPTL3 deficiency (loss-of-function mutations) vs. Individuals without ANGPTL3 loss-of-function mutations was evaluated on Coronary artery disease (OR 0.66, 95% CI 0.44 to 0.98, p=0.04). Heterozygous carrier status for ANGPTL3 loss-of-function mutations was associated with a 34% reduction in odds of coronary artery disease (OR 0.66; 95% CI 0.44 to 0.98; p=0.04).