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 identified both known and novel loci associated with plasma TG concentration. However, genetic variation at these loci explains only ∼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 flesh 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.
Highlights
Plasma triglyceride (TG) concentration is reemerging as an important cardiovascular disease risk factor
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
Using a case-control design comparing ف500 HTG patients with ف1,200 normotriglyceridemic population-based controls [32], we showed genome-wide significant associations among the APOA5, glucokinase regulatory protein (GCKR), lipoprotein lipase (LPL), and APOB loci, and replicated the MLXIPL, TRIB1, Angiopoietin-like 3 protein (ANGPTL3), and NCAN loci, with trends toward significance as determined by P values near significance at the FADS1-FADS2-FADS3 (FADS1-2-3) cluster, XKR6/PINX1, and phospholipid transfer protein (PLTP)
Summary
Hegele1,* Departments of Biochemistry and Medicine,* Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada; and Center for Human Genetic Research and Cardiovascular Research Center,† Massachusetts General Hospital, Boston, MA 02114, Department of Medicine, Harvard Medical School, Boston, MA 02114, and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142
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