Original Investigation
ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

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Abstract

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-function (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.

Key Words

human genetics
loss-of-function mutations
myocardial infarction

Abbreviations and Acronyms

ANGPTL3
angiopoietin-like 3
AU
Agatston units
CAD
coronary artery disease
CCTA
coronary computed tomography angiography
CI
confidence interval
EL
endothelial lipase
HDL
high-density lipoprotein
LDL
low-density lipoprotein
LOF
loss of function
LPL
lipoprotein lipase
MI
myocardial infarction
OR
odds ratio
TG
triglyceride

Cited by (0)

This study was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (R01HL131961 and K08HL114642 to Dr. Stitziel; R01 HL118744 to Dr. Musunuru; and R01 HL127564 and R21 HL120781 to Dr. Kathiresan); the National Human Genome Research Institute (U54HG003067 to Dr. Gabriel and Dr. Lander, UM1HG008895 to Dr. Kathiresan Dr. Gabriel, and Dr. Lander, and UM1HG008853 to Dr. Stitziel); the Barnes-Jewish Hospital Foundation (Dr. Stitziel); the Fannie Cox Prize for Excellence in Science Teaching, Harvard University (Dr. Musunuru); and the MGH Research Scholar Award (Dr. Kathiresan). PROMIS fieldwork has been supported through grants awarded to Dr. Saleheen, Dr. Danesh, and Dr. Frossard. Biomarker assays in PROMIS have been funded through grants awarded by the NHLBI (RC2HL101834 and RC1TW008485) and Fogarty International (RC1TW008485). This work was funded by the National Institutes of Health (NIH), which had no involvement in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, and approval of the manuscript. Dr. Stitziel has received a research grant from AstraZeneca; and consulting fees from Aegerion Pharmaceuticals. Dr. Khera is supported by an American College of Cardiology Foundation/Merck Cardiovascular Research Fellowship, a John S. Ladue Memorial Fellowship at Harvard Medical School, and a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst funded by the NIH (TR001100); and has received consulting fees from Merck and Amarin. Dr. Klarin is supported by the NHLBI (T32 HL007734). Dr. Samani is supported by the British Heart Foundation and is a National Institute for Health Research Senior Investigator. Dr. Rader has received consulting fees from Aegerion Pharmaceuticals, Alnylam Pharmaceuticals, Eli Lilly and Company, Pfizer, Sanofi, and Novartis; is an inventor on a patent related to lomitapide that is owned by the University of Pennsylvania and licensed to Aegerion Pharmaceuticals; and is a cofounder of Vascular Strategies and Staten Biotechnology. Dr. Danesh has received funding from the UK Medical Research Council, British Heart Foundation, UK National Institute of Health Research (NIHR), NIHR Cambridge Comprehensive Biomedical Research, European Commission Framework Programme, European Research Council, GlaxoSmithKline, Merck, NHLBI, NHS Blood and Transplant, Novartis, Pfizer, Wellcome Trust, and UK Biobank. Dr. Saleheen has received grants from Pfizer, Regeneron, Eli Lilly, and Genentech. Dr. Kathiresan has received grants from Bayer Healthcare, Aegerion Pharmaceuticals, and Regeneron Pharmaceuticals; and consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, Quest Diagnostics, Genomics PLC, and Eli Lilly and Company; and holds equity in San Therapeutics and Catabasis Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Stitziel, Khera, Wang, Saleheen, Musunuru, and Kathiresan contributed equally to this work.

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