The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management

Abstract

Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2–10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

“…Intensive lifestyle therapy, including dietary counseling to achieve appropriate diet composition, physical activity, and a program to achieve weight reduction in overweight and obese individuals are the main initial treatment of hypertriglyceridemia and described elsewhere [20,[139][140][141].…”

Extreme hypertriglyceridemia managed with insulin

“…Although the patients in our study were not completely worked up for genetic causes of HTG, it is likely that patients with extreme HTG have some form of underlying genetic defect in lipoprotein metabolism which manifests clinically on interaction with secondary causes such as diabetes, obesity [4,20].…”

Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

“…Monogenic hypercholesterolemias are characterized by elevated lowdensity lipoprotein-cholesterol (LDL-C) levels and very high risk of premature atherosclerotic disease; they are caused by mutations in genes involved in the receptormediated uptake of LDL-C by the LDL receptor (LDLR) in hepatocytes [1]. Primary or genetic forms of hypertriglyceridemia (HTG) with a monogenic etiology include mostly severe forms characterized by the accumulation in plasma of TG-rich lipoproteins (chylomicrons, VLDL and remnant lipoproteins) [2] and an increased risk of developing recurrent episodes of pancreatitis [3].…”