Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia

Praneet K Gill; Jacqueline S Dron; Amanda J Berberich; Jian Wang; Adam D McIntyre; Henian Cao; Robert A Hegele

doi:10.1016/j.jacl.2020.11.006

Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia

J Clin Lipidol. 2021 Jan-Feb;15(1):79-87. doi: 10.1016/j.jacl.2020.11.006. Epub 2020 Nov 24.

Authors

Praneet K Gill¹, Jacqueline S Dron², Amanda J Berberich³, Jian Wang⁴, Adam D McIntyre⁴, Henian Cao⁴, Robert A Hegele⁵

Affiliations

¹ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada.
² Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada.
³ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada.
⁴ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada.
⁵ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street North, London, Ontario N6A 5B7, Canada. Electronic address: hegele@robarts.ca.

PMID: 33303402
DOI: 10.1016/j.jacl.2020.11.006

Abstract

Background: Combined hyperlipidemia (CHL) is a common disorder defined by concurrently elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. Despite decades of study, the genetic basis of CHL remains unclear.

Objective: To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG).

Methods: DNA from 259, 379 and 124 patients with CHL, isolated hypercholesterolemia and isolated HTG, respectively, underwent targeted sequencing. We assessed: 1) rare variants disrupting canonical LDL-C or TG metabolism genes; and 2) two polygenic scores-for elevated LDL-C and TG-calculated using common trait-associated single-nucleotide polymorphisms (SNPs). Genetic profiles were compared against 1000 Genomes Project controls.

Results: Both CHL and isolated HTG patients had significantly increased odds of a high polygenic score for TG: 2.50 (95% confidence interval [CI] 1.61-3.88; P < 0.001) and 3.72 (95% CI 2.24-6.19; P < 0.001), respectively. CHL patients had neither a significant accumulation of rare variants for LDL-C or TG, nor a high polygenic score for LDL-C. In contrast, patients with isolated hypercholesterolemia had a 3.03-fold increased odds (95% CI 2.22-4.13; P < 0.001) of carrying rare variants associated with familial hypercholesterolemia, while patients with isolated HTG had a 2.78-fold increased odds (95% CI 1.27-6.10; P = 0.0136) of carrying rare variants associated with severe HTG.

Conclusion: CHL is genetically similar to isolated HTG, a known polygenic trait. Both cohorts had a significant accumulation of common TG-raising variants. Elevated LDL-C levels in CHL are not associated with common or rare LDL-C-related genetic variants.

Keywords: Cholesterol; Dyslipidemia; Hypercholesterolemia; Hyperlipoproteinemia type IIb; Hypertriglyceridemia; LDL; Monogenic; Polygenic score; Triglycerides.

MeSH terms

Adult
Aged
Cholesterol, LDL / blood
Female
Humans
Hyperlipidemia, Familial Combined / blood
Hyperlipidemia, Familial Combined / genetics
Hyperlipidemias / genetics
Hypertriglyceridemia* / blood
Hypertriglyceridemia* / genetics
Male
Middle Aged
Multifactorial Inheritance / genetics
Polymorphism, Single Nucleotide*
Triglycerides* / blood

Substances

Triglycerides
Cholesterol, LDL

Grants and funding

CIHR/Canada