期刊
JOURNAL OF LIPID RESEARCH
卷 60, 期 9, 页码 1622-1629出版社
ELSEVIER
DOI: 10.1194/jlr.M092809
关键词
apolipoprotein E; atherosclerosis; dyslipidemias; genes; lipid dysfunction; low-density lipoprotein; metabolism; lipidomics
资金
- Academy of Finland [322098, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
- Social Insurance Institution of Finland
- Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku Hospitals [X51001]
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Foundation for Cardiovascular Research
- Finnish Cultural Foundation
- Sigrid Juselius Foundation
- Tampere Tuberculosis Foundation
- Emil Aaltonen Foundation
- Yrjo Jahnsson Foundation
- Signe and Ane Gyllenberg Foundation
- Finnish Diabetes Association
- Pirkanmaa Regional Fund of the Finnish Cultural Foundation
- Tampere University Hospital
- EU [755320]
- European Research Council [742927]
- Tampere and Turku Hospitals [X51001]
apoE, a key regulator of plasma lipids, mediates altered functionalities in lipoprotein metabolism and thus affects the risk of coronary artery disease (CAD). The significance of different apoE polymorphisms remains unclear; although the epsilon 4 allele is clearly associated with increased cholesterol levels (which inform CAD risk), direct studies about apoE polymorphisms on CAD risk and development have yielded controversial results. Furthermore, certain species of ceramides-complex lipids abundant in plasma LDL-are markers of increased risk of myocardial infarction and cardiovascular death. Using a high-throughput MS approach, we quantified 30 molecular plasma ceramide species from a cohort of 2,160 apoE-genotyped (rs7412, rs429358) young adults enrolled in the population-based Cardiovascular Risk in Young Finns Study. We then searched this lipidome data set to identify new indications of pathways influenced by apoE polymorphisms and possibly related to CAD risk. This approach revealed a previously unreported association between apoE polymorphism and a consistently documented high-risk CAD marker, Cer(d18:1/16:0). Compared with the apoE epsilon 3/3 reference group, plasma levels of apoE epsilon 4 were elevated and those of apoE epsilon 2 were lowered in all subjects without evidence of apoE-by-sex interactions. apoE associated with seven ceramides that are connected to atherogenically potent macrophages and/or lipoprotein particles; these associations could indicate a plausible linkage between apoE polymorphism and ceramide metabolism, leading to adverse plasma LDL metabolism and atherogenesis. In conclusion, new evidence from plasma ceramides links apoE polymorphism with an increased risk of CAD and extends our understanding of the role of apoE in health and disease.
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