ANALYSIS OF DNA CHANGES IN THE LPL GENE IN PATIENTS WITH FAMILIAL COMBINED HYPERLIPIDEMIA

Familial combined hyperlipidemia (FCHL) is a common lipid disorder cha racterized by an increase in cholesterol and/or triglyceride levels in multiple individuals of the same family. Prior reports document a dec reased activity of lipoprotein lipase (LPL) in FCHL, and studies of th e role of LPL in the remodeling of nascent lipoproteins suggest that d isturbances in LPL function could underlie FCHL. We studied the LPL ge ne in 31 unrelated individuals with FCHL. A total of 25 DNA changes (1 3 ''silent'' substitutions and 12 DNA changes resulting in amino acid substitutions) were detected in 16 patients. Three new exonic polymorp hisms as well as a previously described Ser(447)-->stop and an Asp(9)- ->Asn substitution were seen with similar frequency on control and FCH L chromosomes. Two novel DNA changes resulting in an Asp(21)-->Val and an His(44)-->Tyr substitution were seen in only two FCHL individuals. In vitro studies showed no effect of these mutations on LPL catalytic activity. LPL mutations impairing catalytic activity did not represen t a significant factor leading to FCHL in this population. Variations in any portion of the coding region of the LPL gene affecting other fu nctions besides catalysis are not a frequent cause of FCHL.