The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants

Elsevier

Available online 22 November 2022

Journal of Clinical LipidologyAuthor links open overlay panelHighlights•

Heterozygotes for pathogenic LPL variants have highly variable TG levels

Heterozygous LPL deficiency and familial hypercholesterolemia are not analogous

There is little to no evidence for autosomal dominant hypertriglyceridemia

Hypertriglyceridemia is genetically complex and almost never mendelian

AbstractBackground

Biallelic pathogenic variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome with severe hypertriglyceridemia (HTG), defined as plasma triglycerides (TG) > 10 mmol/L (> 875 mg/dL). TG levels in individuals with one copy of a pathogenic LPL gene variant is less familiar; some assume that the phenotype is intermediate between homozygotes and controls.

Objective

We undertook an evaluation of the longitudinal TG phenotype of individuals heterozygous for pathogenic LPL variants.

Methods

Medically stable outpatients were evaluated based on having: 1) a single copy of a rare pathogenic LPL variant; and 2) serial fasting TG measurements obtained over > 1.5 years of follow-up.

Results

Fifteen patients with a single pathogenic LPL variant were followed for a mean of 10.3 years (range 1.5 to 30.3 years). TG levels varied widely both within and between patients. One patient had normal TG levels < 2.0 mmol/L (< 175 mg/dL) continuously, while four patients had at least one normal TG level. Most patients fluctuated between mild-to-moderate and severe HTG: five patients had only mild-to-moderate HTG, with TG levels ranging from 2.0 to 9.9 mmol/L (175 to 875 mg/dL), while 6 patients had at least one instance of severe HTG. Of the 203 total TG measurements from these patients, 14.8%, 67.0% and 18.2% were in the normal, mild-to-moderate and severe HTG ranges, respectively.

Conclusion

The heterozygous LPL deficient phenotype is highly variable both within and between patients. Heterozygosity confers susceptibility to a wide range of TG phenotypes, with severity likely depending on secondary factors.

Keywords

complex trait

familial chylomicronemia syndrome

hyperlipoproteinemia type 1

hyperlipoproteinemia type 5

multifactorial chylomicronemia syndrome

hypertriglyceridemia

lipoprotein lipase deficiency

next-generation DNA sequencing

pathogenic variant

© 2022 Published by Elsevier Inc. on behalf of National Lipid Association.

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