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

Atherosclerosis. 2021 Jul:328:144-152. doi: 10.1016/j.atherosclerosis.2021.04.015. Epub 2021 May 9.

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.

Keywords: Cardiovascular disease; LDL-Cholesterol-lowering; Lipoprotein lipase; Mendelian randomization; Metabolomics; Triglyceride-lowering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Cholesterol, LDL / genetics
  • Lipase*
  • Lipoprotein Lipase* / genetics
  • Lipoproteins
  • Netherlands
  • Triglycerides

Substances

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