Dorina Ibi1, Lisanne L Blauw2, Raymond Noordam3, Martijn E T Dollé4, J Wouter Jukema5, Frits R Rosendaal6, Constantinos Christodoulides7, Matt J Neville8, Robert Koivula7, Patrick C N Rensen2, Fredrik Karpe8, Ko Willems van Dijk9. 1. Dept. Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Dept. Public Health and Primary Care, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Electronic address: d.ibi@lumc.nl. 2. Dept. Internal Medicine, Div. Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands. 3. Dept. Internal Medicine, Div. Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. 4. Dept. Public Health and Primary Care, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. 5. Dept. Cardiology, Leiden University Medical Center, Leiden, the Netherlands. 6. Dept. Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. 7. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom. 8. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, United Kingdom. 9. Dept. Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Dept. Internal Medicine, Div. Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
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.
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; Manon Boot; Martijn E T Dollé; J Wouter Jukema; Frits R Rosendaal; Constantinos Christodoulides; Matt J Neville; Robert Koivula; Patrick C N Rensen; Fredrik Karpe; Raymond Noordam; Ko Willems van Dijk Journal: J Lipid Res Date: 2022-03-10 Impact factor: 6.676