Severe hypertriglyceridemia is primarily polygenic

Jacqueline S Dron; Jian Wang; Henian Cao; Adam D McIntyre; Michael A Iacocca; Jyler R Menard; Irina Movsesyan; Mary J Malloy; Clive R Pullinger; John P Kane; Robert A Hegele

doi:10.1016/j.jacl.2018.10.006

Severe hypertriglyceridemia is primarily polygenic

J Clin Lipidol. 2019 Jan-Feb;13(1):80-88. doi: 10.1016/j.jacl.2018.10.006. Epub 2018 Oct 24.

Authors

Affiliations

¹ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
² Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
³ Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada.
⁴ Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
⁵ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: hegele@robarts.ca.

PMID: 30466821
DOI: 10.1016/j.jacl.2018.10.006

Abstract

Background: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.

Objective: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.

Methods: We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants.

Results: As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P < .0001) more likely to carry one of these types of genetic susceptibility compared with controls.

Conclusions: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG.

Keywords: Copy-number variants (CNVs); Familial chylomicronemia syndrome (FCS); Hypertriglyceridemia (HTG); Monogenic; Next-generation sequencing (NGS); Polygenic; Polygenic risk score; Rare variants; Single-nucleotide polymorphism (SNP).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Apolipoprotein C-II / genetics
Cohort Studies
Disease Progression
Dyslipidemias / genetics
Female
Genetic Predisposition to Disease
Genotype*
High-Throughput Nucleotide Sequencing
Humans
Hypertriglyceridemia / genetics*
Lipoprotein Lipase / genetics
Male
Middle Aged
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Receptors, Lipoprotein / genetics

Substances

Apolipoprotein C-II
GPIHBP1 protein, human
Receptors, Lipoprotein
LPL protein, human
Lipoprotein Lipase

Grants and funding

CIHR/Canada