Key result
APOA5 variants reduce LPL activation up to ~36% vs wild type, partly explaining high TG.
Why the study?
Rare APOA5 variants in patients with severe hypertriglyceridemia were identified but their functional impact on lipoprotein lipase activity and receptor binding was unclear.
Observational (n=130)
In vitro functional testing of rare APOA5 variants shows reduced LPL activation or receptor binding, but these defects only partly explain the severe hypertriglyceridemia phenotype, suggesting a need for co-inheritance of other variants.
Partial LPL defects from APOA5 variants warrant caution in phenotype attribution; leaves open co-inheritance of modifiers in severe hypertriglyceridemia.
OBJECTIVE: The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. METHODS AND RESULTS: We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -Delta139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (-25% [P=0.005], -36% [P<0.0001], and -23% [P=0.02]), respectively). ApoAV-C271, -X139, -X148, and Delta139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. CONCLUSIONS: The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans, appears to be essential for their phenotypic expression.
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Dorfmeister et al. (2008) conducted an observational in Severe hypertriglyceridemia (n=130). Rare APOA5 variants vs. Wild type was evaluated on In vitro LPL activity and receptor binding. Compared to wild type, APOA5 variants apoAV-G255, -L321, and -C185 showed reduced LPL activation (-25%, -36%, and -23%, respectively), which only partly explains the high TG levels in carriers.
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