Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia.
Cholesterol
Dyslipidemia
Hypercholesterolemia
Hyperlipoproteinemia type IIb
Hypertriglyceridemia
LDL
Monogenic
Polygenic score
Triglycerides
Journal
Journal of clinical lipidology
ISSN: 1933-2874
Titre abrégé: J Clin Lipidol
Pays: United States
ID NLM: 101300157
Informations de publication
Date de publication:
Historique:
received:
12
09
2020
revised:
24
10
2020
accepted:
17
11
2020
pubmed:
12
12
2020
medline:
26
11
2021
entrez:
11
12
2020
Statut:
ppublish
Résumé
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. To characterize the genetic profiles of patients with CHL and compare them to those in patients with isolated hypercholesterolemia and isolated hypertriglyceridemia (HTG). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33303402
pii: S1933-2874(20)30332-9
doi: 10.1016/j.jacl.2020.11.006
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
79-87Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.