Recent Insights into the Genetics of Plasma Triglycerides and Possible Causal Mechanisms in Cardiovascular Disease

Abstract

Plasma triglyceride (TG) concentration is an integrated measurement of circulating TG‐rich lipoproteins. The specific lipoprotein fractions and subfractions that contribute to this measurement differ between the fasting and nonfasting states. Although the association between fasting plasma TG concentration and cardiovascular disease (CVD) has been controversial, recent studies of nonfasting plasma TG and related biomarkers have rekindled interest in a possible direct causative relationship. Here, we review current understanding of the phenotypic and genetic spectrum of plasma TG concentrations, focusing on recent evidence from Mendelian randomisation studies that seem to implicate nonfasting TG and remnant cholesterol in CVD susceptibility. The totality of evidence suggests that nonfasting TG concentration, perhaps because of its relationship with remnant cholesterol, is causally associated with CVD outcomes.

Key Concepts:

  • Susceptibility to clinical hypertriglyceridaemia is determined by a burden of both common and rare variants, on which are superimposed secondary nongenetic factors.

  • The allelic and phenotypic spectrum of plasma triglyceride (TG) concentrations explains a variety of TG‐related phenotypes and their phenotypic heterogeneity.

  • Monogenic hypertriglyceridemias are associated with increased pancreatitis risk and result from rare mutations on both alleles of 6 different genes.

  • Nonfasting plasma TG concentration is closely associated with elevated remnant cholesterol concentrations; this may explain the relationship with cardiovascular risk.

  • Mendelian randomisation studies appear to implicate a causal relationship between both nonfasting plasma TG, and more recently remnant cholesterol levels as determinants of CVD risk.

  • The spectrum of genes newly implicated as being involved in plasma triglyceride metabolism has expanded the range of pathways and potential drug targets.

Keywords: genetic variation; plasma triglyceride; hypertriglyceridaemia; hyperlipoproteinaemia; nonfasting plasma triglyceride; remnant cholesterol; mendelian randomisation; cardiovascular disease

Figure 1.

Contribution of genetic variants in TG‐associated genes to the allelic and phenotypic spectrum of plasma TG concentrations. Cells are shaded to indicate the relative contribution of common and rare variants to each respective TG phenotype. Monogenic phenotypes are caused by rare homozygous variants of individually large effect, whereas the contribution of common variants is much less relevant in these conditions, which are often paediatric. Polygenic phenotypes are caused by a combination of rare and common variants, either in genes that inhibit or modulate TG‐metabolism causing very low plasma TG, or in genes that are essential to metabolise TG‐rich lipoproteins causing very high plasma TG. Normal TG concentrations are caused by a balance of both common and rare variants of individually small effect, in genes that either increase or decrease plasma TG concentrations. This model is simplified: TG phenotypes are arbitrarily defined, but truly represent a spectrum of phenotypes dependent on underlying variation. However, each phenotype depends on the relative contribution of common and rare variants found in any number of genes. Cells containing question marks indicate assumed gene involvement in a phenotype, where results have never been proven.

Figure 2.

The allelic spectrum of plasma TG concentrations explains hypertriglyceridaemia (hyperTG) susceptibility and phenotypic heterogeneity among the classically defined hyperlipoproteinaemia (HLP) phenotypes. A balance of normal and protective TG‐associated risk alleles results in normal TG concentrations, whereas an accumulation of TG‐associate risk alleles provides a foundation of hyperTG susceptibility. A critical accumulation of common variants (CV), rare variants (RV) and secondary environmental exposures (such as diet, obesity, metabolic syndrome (MetS) or type 2 diabetes (T2D)) is sufficient to cause expression of HLP type 4 (hypertriglyceridaemia). The accumulation of TG‐associated common variants that are jointly associated with low‐density lipoprotein cholesterol (LDL‐C) transform HLP type 4 into HLP type 2b (combined hyperlipidaemia). The presence of two receptor‐binding defective APOE E2 alleles on a background of susceptibility to hyperTG hastens manifestation of the HLP type 3 (dysbetalipoproteinaemia) phenotype. Finally, the added effects of particularly damaging mutations, heterozygous APOE E2 alleles and extreme secondary factors push the phenotypes towards the more extreme HLP type 5 (mixed hyperlipidaemia).

Figure 3.

Schematic of the Mendelian randomisation (MR) framework and possible sources of confounding relating to TG‐rich lipoprotein metabolism. MR presumes that if a genetic variant or genetic risk score (GRS) is proportionally associated with both an intermediate trait and disease endpoint, then a causal relationship likely exists between the trait and disease endpoint. However, biological confounders including linkage disequilibrium and pleiotropy may interfere with such presumptions of causality if the genetic instrument is associated with other metabolic pathways or other genes with their own involvement in disease pathophysiology.

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Further Reading

McPherson R (2013) Remnant cholesterol: “Non‐(HDL‐C+LDL‐C)” As a coronary artery disease risk factor. Journal of the American College of Cardiology 61(4): 437–439.

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Johansen, Christopher T, MacDonald, Austin, and Hegele, Robert A(Dec 2013) Recent Insights into the Genetics of Plasma Triglycerides and Possible Causal Mechanisms in Cardiovascular Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025307]