Primary Hypertriglyceridemia

Abstract

Hypertriglyceridemia (HTG) is a common clinical and biochemical diagnosis. HTG clusters in families, but usually does not show classical Mendelian patterns of inheritance. The exception is “familial chylomicronemia,” in which severe HTG results from autosomal recessive inheritance rare loss-of-function mutations in genes such as lipoprotein lipase (LPL), apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), lipase maturation factor 1 (LMF1), and glycosyl-phosphatidyl-inositol-anchored HDL-binding protein (GPIHBP1). In contrast, common primary HTG in most patients is polygenic rather than monogenic—including those with such classical “familial” phenotypes as combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4), and mixed hyperlipidemia (HLP type 5). These latter four polygenic phenotypes are similar at the genetic level, and result from accumulation of multiple common small-effect genetic variants—single-nucleotide polymorphisms—together with occasional heterozygous rare large-effect variants. Here, we discuss molecular genetic, clinical, and therapeutic aspects of the HTG disorders, except for familial combined hyperlipoproteinemia, which is discussed elsewhere.