The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants

Area of Science:

• Genetics
• Metabolic Disorders
• Cardiovascular Disease

Background:

• Familial chylomicronemia syndrome (FCS) is caused by biallelic pathogenic variants in the lipoprotein lipase (LPL) gene, leading to severe hypertriglyceridemia (HTG).
• The triglyceride (TG) phenotype associated with heterozygous LPL variants is less understood, with assumptions of an intermediate phenotype.

Purpose of the Study:

• To evaluate the longitudinal triglyceride (TG) phenotype in individuals who are heterozygous for pathogenic LPL variants.
• To characterize the variability and range of TG levels in LPL heterozygotes.

Main Methods:

• Longitudinal evaluation of medically stable outpatients carrying a single copy of a rare pathogenic LPL variant.
• Serial fasting TG measurements were collected over a follow-up period exceeding 1.5 years.

Main Results:

• Fifteen patients with a single pathogenic LPL variant were followed for a mean of 10.3 years.
• Triglyceride (TG) levels exhibited significant intra- and inter-patient variability.
• While one patient maintained normal TG levels, others fluctuated between normal, mild-to-moderate HTG, and severe HTG, with 18.2% of measurements indicating severe HTG.

Conclusions:

• The phenotype of heterozygous LPL deficiency is highly variable.
• LPL heterozygosity predisposes individuals to a broad spectrum of TG phenotypes.
• The severity of HTG in LPL heterozygotes likely depends on secondary contributing factors.