The Polygenic Nature of Hypertriglyceridaemia: Implications for Definition, Diagnosis and Management

Plasma triglyceride concentration is a biomarker of circulating triglyceride-rich lipoproteins and their
metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and
determined by the cumulative burden of common and rare variants in >30 genes, as quantified by
genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from
mutations of large effect in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic
factors. Based on recent genetic data, we re-define two hypertriglyceridaemic states: (i) severe (>10
mmol/L), more likely to have a monogenic cause, and (ii) mild-to-moderate (2 to 10 mmol/L). Due to
clustering of susceptibility alleles and secondary factors in families, biochemical screening and
counselling of family members is essential, while routine genetic testing is not warranted. Treatment
includes management of lifestyle and secondary factors, and pharmacotherapy. In severe
hypertriglyceridaemia, intervention is indicated due to pancreatitis risk, and in mild-to-moderate
hypertriglyceridaemia, is aimed at preventing cardiovascular disease, depending on triglyceride
elevation, concomitant lipoprotein disturbances, and overall cardiovascular risk.