MUTATIONS IN THE GENE FOR LIPOPROTEIN-LIPASE - A CAUSE FOR LOW HDL CHOLESTEROL LEVELS IN INDIVIDUALS HETEROZYGOUS FOR FAMILIAL HYPERCHOLESTEROLEMIA

Familial hypercholesterolemia (FH) is characterized by elevated plasma concentrations of LDL cholesterol resulting from mutations in the gen e for the LDL receptor. Low HDL cholesterol levels are seen frequently in patients bath heterozygous and homozygous for mutations in this ge ne. Suggested mechanisms for reduced HDL levels in FH patients have be en altered apolipoprotein A-1 metabolism and elevated cholesteryl este r transfer protein activity, but the molecular basis for hypoalphalipo proteinemia in any of these patients has not yet been identified. We i nvestigated four large families in which individuals were found to be double heterozygotes for both FH and lipoprotein lipase (LPL) deficien cy. These double heterozygotes have significantly less HDL cholesterol than persons with FH or LPL heterozygosity alone. In the double heter ozygotes, HDL particle composition is not significantly different from FH heterozygotes, suggesting a quantitative rather than qualitative d efect in HDL metabolism in these persons. We propose that mutations in the LPL gene may be a cause of low HDL cholesterol levels in some ind ividuals heterozygous for FH.