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

Abstract

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.