Genetic determinants of plasma triglycerides

Abstract

Supplementary key words hypertriglyceridemia • hypotriglyceridemia • dyslipidemias • genetic variation • genomics • lipoproteins • resequencingPlasma triglyceride (TG) concentration is a complex polygenic trait that follows a rightward-skewed distribution in the population ( Fig. 1 ).As a clinical measurement, it integrates multiple TG-rich lipoprotein (TRL) species that circulate in plasma, predominantly intestinally synthesized chylomicrons (CMs) in the postprandial state and hepatically synthesized very low density lipoproteins (VLDL) in the fasted state.Epidemiological evidence indicates that plasma TG concentration is a strong independent risk factor for cardiovascular disease (CVD), suggesting that prolonged residence of plasma TRLs, especially in the postprandial state, may contribute to CVD susceptibility ( 1-7 ).Together with environmental infl uences, common and rare variants in multiple genes may collectively determine a patient's plasma TG concentration.Identifying genes and genetic variants associated with plasma TG concentration will enrich our understanding of biochemical pathways involved in TRL metabolism, enabling identifi cation of Abstract Plasma triglyceride (TG) concentration is reemerging as an important cardiovascular disease risk factor.More complete understanding of the genes and variants that modulate plasma TG should enable development of markers for risk prediction, diagnosis, prognosis, and response to therapies and might help specify new directions for therapeutic interventions.Recent genome-wide association studies (GWAS) have identifi ed both known and novel loci associated with plasma TG concentration.However, genetic variation at these loci explains only ‫ف‬ 10% of overall TG variation within the population.As the GWAS approach may be reaching its limit for discovering genetic determinants of TG, alternative genetic strategies, such as rare variant sequencing studies and evaluation of animal models, may provide complementary information to fl esh out knowledge of clinically and biologically important pathways in TG metabolism.Herein, we review genes recently implicated in TG metabolism and describe how some of these genes likely modulate plasma TG concentration.We also discuss lessons regarding plasma TG metabolism learned from various genomic and genetic experimental approaches.Treatment of patients with moderate to severe hypertriglyceridemia with existing therapies is often challenging; thus, gene products and pathways found in recent genetic research studies provide hope for development of more effective clinical strategies.-Johansen, C. T., S. Kathiresan, and R. A. Hegele.Genetic determinants of plasma triglycerides.J. Lipid Res.