November 2, 2010Journal of Lipid Research262 citationsOpen Access
Genetic determinants of plasma triglycerides
Key Result
Genetic variation at loci identified by genome-wide association studies explains only 10% of overall plasma triglyceride variation within the population.
Key Points
- The research aims to identify genetic determinants influencing plasma triglyceride (TG) concentrations and their implications for cardiovascular disease risk.
- Conducted genome-wide association studies (GWAS) to identify loci associated with plasma TG concentration.
- Reviewed recent findings on genes implicated in TG metabolism and their effects on plasma TG levels.
- Evaluated alternative genetic approaches for a more comprehensive understanding of TG metabolism.
- Identified both known and novel loci associated with plasma TG concentration; however, they account for only 10% of overall TG variation in the population.
- Proposed that alternative approaches, like rare variant sequencing and animal models, may clarify important pathways in TG metabolism.
- Discussed challenges in treating patients with hypertriglyceridemia, emphasizing potential new therapeutic strategies from genetic findings.
PICO
P
Population
Hypertriglyceridemia
E
Exposure / Comparator
Genetic variation
Abstract
Plasma triglyceride (TG) concentration is a complex polygenic trait that follows a rightward-skewed distribution in the population ( Fig. 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 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. -