Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies

Abstract

Lipoproteins are a major risk factor for atherosclerotic cardiovascular diseases (ASCVD). Among the lipoproteins, low-density lipoproteins (LDL) have been shown to be causally associated with ASCVD development. In contrast, triglycerides or triglyceride-rich lipoproteins receive less attention than LDL because there is little definite evidence from randomized controlled trials. A Mendelian randomization study has recently been published in which a causal association could be estimated with observational datasets. Using such Mendelian randomization studies, ranging from common to rare genetic variations, triglycerides seem to be causally associated with ASCVD outcomes independent of LDL. Although the "causal association" of serum triglycerides and ASCVD is difficult to assert, accumulated evidence from clinical and Mendelian randomization studies, using common and rare genetic variations, strongly supports such an association. In this article, we provide a summary of investigations focusing on important causal associations between serum triglycerides and ASCVD from the clinical point of view.

Keywords: cholesterol; genetics; remnant lipoproteins; triglycerides.

Figure 1

Lipid content of each lipoprotein. Light blue indicates cholesterol. Orange indicates triglycerides. Pink indicates phospholipid. Black indicates apolipoprotein. Chylomicron, very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) are recognized as triglyceride-rich lipoproteins, and LDL is regarded as cholesterol lipoprotein.

Figure 2

Scheme of randomized controlled trial and Mendelian randomization studies. The left panel indicates a randomized controlled trial. The right panel indicates a Mendelian randomized study. In a randomized controlled trial, participants are typically randomized either to placebo or actual drug, then we measure blood markers and associated outcomes. In this case, we can assume that intervention using particular drug associated with changes in blood marker lead to the changes in outcomes. On the other hand, in a Mendelian randomized study, participants are randomized to particular alleles, then we measure blood markers and associated outcomes. In this case, we can regard it as a proxy of a randomized controlled trial.

Figure 3

Cardiac events and triglycerides under statin therapies. The left panel shows short-term events after acute coronary syndrome (The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering: MIRACLE study). The subjects were divided according to tertiles of baseline triglyceride levels. The right panel shows the long-term events in the primary prevention group (standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopathy: EMPATHY study). The subjects were divided according to quintiles of baseline triglyceride levels. Both results strongly suggest that triglyceride is a residual risk factor under sufficient statin therapy for the development of ASCVD.

Figure 4

LPL pathway and associated proteins. Major proteins associated with LPL pathway are illustrated in this scheme. LPL is transported to endothelial cells, and binds to GPIHBP1. LPL hydrolyzes triglycerides on lipoproteins. APOC3, angiopoietin-like protein 3 (ANGPTL3), and angiopoietin-like protein 4 (ANGPTL4) play as inhibitor of LPL. On the other hand, APOC2 and APOA5 activate LPL. The fact that those proteins are significantly associated with ASCVD strongly suggests that LPL pathway is associated with the development of ASCVD.