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.

Figure 1. Redefinition of hypertriglyceridaemic states on the basis of new genetic data

Triglyceride concentrations of more than 10 mmol/L, especially in young patients, are more likely to be due to monogenic causes combined with secondary factors, whereas patients with triglyceride concentrations of 2–10 mmol/L represent a single group, based on the interplay of several genes (both heterozygous mutations of large effect, and the cumulative burden of small-effect variants, causing a high genetic risk score; figure 2), together with secondary factors. Plasma triglyceride concentrations and approximate population percentages are based on data for more than 70 000 adults (>20 years of age) from the Copenhagen General Population Study.

Figure 2. Genetic risk scores for triglyceride-associated risk alleles

Unweighted risk scores composed of risk alleles at 32 triglyceride-associated loci were summed across individuals and compared between patients with hypertriglyceridaemia and controls. The minimum unweighted risk score is 0, whereas the maximum unweighted risk score is 64, but most scores in the population range between 22 and 46. Compared with healthy controls, the relative frequency distribution of triglyceride genetic risk scores was significantly increased in 504 patients with hypertriglyceridaemia (p=1·6×10⁻⁵³). Figure reproduced from Johansen and colleagues by permission of Elsevier.