Triglyceride-lowering LPL alleles combined with LDL-C-lowering alleles are associated with an additively improved lipoprotein profile.

Abstract

BACKGROUND AND AIMS:

Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles.

METHODS:

We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference.

RESULTS:

Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower.

CONCLUSIONS:

Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.

• Authors: Dorina Ibi, Lisanne L Blauw, Raymond Noordam, Martijn E T Dollé, J Wouter Jukema, Frits R Rosendaal, Constantinos Christodoulides, Matt J Neville, Robert Koivula, Patrick C N Rensen, Fredrik Karpe, Ko Willems van Dijk
• Journal: Atherosclerosis (Atherosclerosis) Vol. 328 Pg. 144-152 (07 2021) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 34053745 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Cholesterol, LDL
• Lipoproteins
• Triglycerides
• Lipase
• Lipoprotein Lipase

Topics

• Alleles
• Cholesterol, LDL (genetics)
• Lipase
• Lipoprotein Lipase (genetics)
• Lipoproteins
• Netherlands
• Triglycerides