Author + information
- Received February 21, 2019
- Revision received May 1, 2019
- Accepted May 7, 2019
- Published online July 22, 2019.
- Mark Trinder, MSca,b,
- Xuan Li, MSca,
- Maria Liza DeCastro, BSca,
- Luba Cermakova, MSca,
- Singh Sadananda, PhDc,
- Linda M. Jackson, BSca,
- Hawmid Azizi, MSca,
- G.B. John Mancini, MDa,
- Gordon A. Francis, MDa,d,
- Jiri Frohlich, MDa and
- Liam R. Brunham, MD, PhDa,b,d,∗ (, )@LiamBrunham
- aCentre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada
- bExperimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada
- cSchool of Biology, Indian Institute of Science Education and Research-Trivandrum, Trivandrum, Kerala, India
- dDepartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- ↵∗Address for correspondence:
Dr. Liam R. Brunham, Centre for Heart Lung Innovation, Room 166-1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
Background A pathogenic variant in LDLR, APOB, or PCSK9 can be identified in 30% to 80% of patients with clinically-diagnosed familial hypercholesterolemia (FH). Alternatively, ∼20% of clinical FH is thought to have a polygenic cause. The cardiovascular disease (CVD) risk associated with polygenic versus monogenic FH is unclear.
Objectives This study evaluated the effect of monogenic and polygenic causes of FH on premature (age <55 years) CVD events in patients with clinically diagnosed FH.
Methods Targeted sequencing of genes known to cause FH as well as common genetic variants was performed to calculate polygenic scores in patients with “possible,” “probable,” or “definite” FH, according to Dutch Lipid Clinic Network Criteria (n = 626). Patients with a polygenic score ≥80th percentile were considered to have polygenic FH. We examined the risk of unstable angina, myocardial infarction, coronary revascularization, or stoke.
Results A monogenic cause of FH was associated with significantly greater risk of CVD (adjusted hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.12; p = 0.004), whereas the risk of CVD in patients with polygenic FH was not significantly different compared with patients in whom no genetic cause of FH was identified. However, the presence of an elevated low-density lipoprotein cholesterol (LDL-C) polygenic risk score further increased CVD risk in patients with monogenic FH (adjusted hazard ratio: 3.06; 95% confidence interval: 1.56 to 5.99; p = 0.001).
Conclusions Patients with monogenic FH and superimposed elevated LDL-C polygenic risk scores have the greatest risk of premature CVD. Genetic testing for FH provides important prognostic information that is independent of LDL-C levels.
This study was supported by a Sector Improvement Project award from Genome British Columbia, and an infrastructure grant from the Canada Foundation for Innovation (both to Dr. Brunham). The British Columbia FH Registry was supported by investigator-initiated awards from Sanofi Canada and Amgen Canada. Dr. Trinder is supported by a Vanier Canada Graduate Scholarship. Dr. Mancini has received honoraria, consulting fees, and grants from Amgen and Sanofi; and has received consulting fees from Esperion. Dr. Francis has served as an Advisory Board member for Akcea. Dr. Brunham is a CIHR New Investigator, a Michael Smith Foundation for Health Research scholar, and a Canada Research Chair in Precision Cardiovascular Disease Prevention. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received February 21, 2019.
- Revision received May 1, 2019.
- Accepted May 7, 2019.
- 2019 American College of Cardiology Foundation
This article requires a subscription or purchase to view the full text. If you are a subscriber or member, click Login or the Subscribe link (top menu above) to access this article.