Abstract
Apolipoprotein E (apoE) is the key regulator of plasma lipids, mediating altered functionalities in lipoprotein metabolism – affecting the risk of coronary artery (CAD) and Alzheimer’s diseases, as well as longevity. Searching pathways influenced by apoE prior to adverse manifestations, we utilized a metabolome dataset of 228 nuclear-magnetic-resonance-measured serum parameters with a 10-year follow-up from the population-based Young Finns Study cohort of 2,234 apoE-genotyped (rs7412, rs429358) adults, aged 24–39 at baseline. At the end of our follow-up, by limiting FDR-corrected p < 0.05, regression analyses revealed 180/228 apoE-polymorphism-related associations with the studied metabolites, in all subjects – without indications of apoE x sex interactions. Across all measured apoE- and apoB-containing lipoproteins, ε4 allele had consistently atherogenic and ε2 protective effect on particle concentrations of free/esterified cholesterol, triglycerides, phospholipids and total lipids. As novel findings, ε4 associated with glycoprotein acetyls, LDL-diameter and isoleucine – all reported biomarkers of CAD-risk, inflammation, diabetes and total mortality. ApoE-subgroup differences persisted through our 10-year follow-up, although some variation of individual metabolite levels was noticed. In conclusion, apoE polymorphism associate with a complex metabolic change, including aberrations in multiple novel biomarkers related to elevated cardiometabolic and all-cause mortality risk, extending our understanding about the role of apoE in health and disease.
Highlights
Apolipoprotein E is a glycoprotein consisting of 299 amino acids, and it functions as the key regulator of plasma lipid levels
Our cross-sectional results of Apolipoprotein E (apoE) genotype effects on serum lipid and lipoprotein metabolites in all subjects are consistently in line with the metabolic mechanisms reviewed in detail in[6,32,33]
After fat ingestion the shifting of apoE proteins between lipoproteins, as well as lipoprotein conversion and production rates are all suggested to depend on the apoE phenotypes
Summary
Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. 3Department of Medicine, University of Turku, and Division of Medicine, Turku University Hospital, Turku, Finland, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia. 4Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland. 5NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland. 6Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK. 7Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK. 8Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. 9Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, VIC, Australia. 10Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. 11Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular. Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. Two single-nucleotide polymorphisms (SNPs, rs429358 and rs7412) at locus 19q13.31 determine three common allelic variants of the apoE gene: ε2, ε3 and ε4. These alleles code three protein isoforms: E2, E3 and E4. Further research is needed on clarifying the metabolic pathways and mechanisms of the pathogenesis of CAD – as well as on the role of genetic control, including apoE
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