Genetic risk of hypertriglyceridaemia

Severe hypertriglyceridaemia (HTG) – ie. fasting triglyceride (TG) levels >10 mmol/L – is seen in 1 in 400 to 500 people and can have either a monogenic or polygenic basis.¹ Mild-to-moderate HTG – ie. TG from 2 to 9.9 mmol/L – is seen in 25-30% of the population and is usually polygenic.²

A subset of severe HTG is familial chylomicronaemia syndrome (FCS, formerly hyperlipoproteinaemia [HLP] type 1).  FCS is an autosomal recessive condition with a prevalence of 1 to 10 per million. It is caused by rare, biallelic (i.e. homozygous or compound heterozygous) loss-of-function variants in one of five genes: LPL encoding lipoprotein lipase (80-90% of cases), GPIHBP1 (~5% of cases), APOA5 (~5% of cases), APOC2 (~2% of cases), and LMF1 (<1% of cases).  FCS presents in infancy or childhood and the major risk to health is pancreatitis.  Genetic testing should be performed if the diagnosis of FCS is suspected.

In contrast, most adults with severe HTG have polygenic or multifactorial chylomicronaemia syndrome (MCS; formerly HLP type 5).  Patients with MCS have an excess of rare heterozygous variants in one of the five FCS genes plus accumulated common DNA variants – single nucleotide polymorphisms or SNPs – associated with small increases in TG levels identified in genome-wide association studies. An individual’s genetic burden is quantified by a polygenic SNP score for TG, although polygenic scores are still only for research and not clinical use.

Mild-to-moderate HTG (former type HLP 4) is polygenic in nature, with both heterozygous rare variants and common SNPs but a lower total burden than in severe HTG.  Patients with dysbetalipoproteinaemia (former type HLP 3) have mild-to-moderate HTG plus hypercholesterolaemia; this condition is also polygenic, together with APOE E2/E2 homozygosity or a rare APOE gene mutation.  Patients with combined hyperlipidaemia (former type HLP 2B) also have mild-to-moderate HTG in combination with hypercholesterolaemia; this is another polygenic condition. 

Secondary factors including diabetes, obesity, alcohol use, liver disease and renal disease can worsen expression of HTG, whether mild-to-moderate or severe or monogenic or polygenic.

References

1. Hegele RA, Ginsberg HN, Chapman MJ et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diab Endocrinol 2014; 2: 655-666.
2. Dron JS, Hegele RA. Genetics of hypertriglyceridemia. Front Endocrinol. 2020; 11:455.