Genetic determinants of plasma triglycerides

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.

Fig. 1.

Frequency distribution of fasting plasma triglyceride (TG) concentrations. White bars represent male subjects, and black bars represent female subjects. Subjects with plasma TG concentration >3.37 mmol·l⁻¹ are in the 95th percentile, considered the threshold for hypertriglyceridemia (HTG). To convert mmol·l⁻¹ to mg·dl⁻¹, multiply by 88.6. The maximum plasma TG concentration in this sample was 45 mmol·l⁻¹. Data were obtained from the Canadian Heart Health Survey, a cross-sectional population-based study including >26,000 participants of multiple ancestries and ages from 18 to 74 years old, from metropolitan, urban, and rural areas of Canada (170).

Fig. 2.

An increased genetic burden of triglyceride (TG)-raising alleles is characteristic of hypertriglyceridemia (HTG). Unweighted risk scores were constructed from the sum of TG-raising alleles at 32 TG-associated loci (19), generating a minimum possible score of 0 and a maximum possible score of 64; actual risk scores ranged between 26 and 47 alleles in HTG patients and 27 and 45 alleles in controls. Risk scores were compared among risk score bins in 344 HTG patients and 144 controls by using Fisher's exact test; the P value is derived from the Cochrane-Armitage test for trend. These results were generated based on the HTG subject cohort reported in the GLGC (19) but without adjustment for population-based effect estimates or clinical covariates. CI, confidence interval.

Fig. 3.

Sequence of experimental approaches required to achieve clinical benefit from current TG-associated loci.