ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

作者：Stitziel, Nathan O.; Khera, Amit V.; Wang, Xiao; Bierhals, Andrew J.; Vourakis, A. Christina; Sperry, Alexandra E.; Natarajan, Pradeep; Klarin, Derek; Emdin, Connor A.; Zekavat, Seyedeh M.; Nomura, Akihiro; Erdmann, Jeanette; Schunkert, Heribert; Samani, Nilesh J.; Kraus, William E.; Shah, Svati H.; Yu, Bing; Boerwinkle, Eric; Rader, Daniel J.; Gupta, Namrata; Frossard, Philippe M.; Rasheed, Asif; Danesh, John; Lander, Eric S.; Gabriel, Stacey; Saleheen, Danish; Musunuru, Kiran

来源：Journal of the American College of Cardiology, 2017, 69(16): 2054-2063.

DOI：10.1016/j.jacc.2017.02.030

• human genetics
• loss-of-function mutations
• myocardial infarction

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 patients with myocardial infarction (MI)-to test whether 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-LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. 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 people who presented with MI and 3,232 control subjects. @@@ RESULTS The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with 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.

• 出版日期2017-4-25