Heterozygosity for Asn291-->Ser mutation in the lipoprotein lipase gene in two Finnish pedigrees: effect of hyperinsulinemia on the expression of hypertriglyceridemia.

We describe two Finnish kindreds with the Asn291 --> Ser mutation (A291S) of the lipoprotein lipase (LPL) gene. Sixteen subjects (9 male, 7 female) heterozygous for this mutation were studied and compared with 17 unaffected family members or spouses (family controls) and 19 unrelated healthy subjects (population controls). In the group of subjects heterozygous for the A291S mutation, postheparin plasma LPL activity was on average 23% lower than in the family controls and 29% lower than in the population controls. In agreement, in vitro expression studies with COS-7 cells showed that the mutant protein exhibits approximately 50% of the lipolytic activity of the wild-type protein. Median serum triglyceride concentration was 2.90 mmol/l in the group of heterozygotes, compared with 1.14 mmol/l in the family controls (P < 0.01) and 0.99 mmol/l in the population controls (P < 0.001). The heterozygotes also had a marked preponderance of small dense low density lipoproteins (LDL) as assessed by gradient gel electrophoresis. Nine of the heterozygous subjects were hypertriglyceridemic (serum triglyceride concentration > 2.0 mmol/l). Age or body mass index were not related to the presence of hypertriglyceridemia. By contrast, all hypertriglyceridemic subjects were either hyperinsulinemic (serum insulin concentration > 10 mU/l, n = 7) or had diabetes (n = 2). In a multivariate regression analysis, very low density lipoprotein (VLDL) triglyceride level was significantly and independently related to serum apolipoprotein B concentration, the presence of the A291S mutation, serum insulin concentration, and postheparin plasma LPL activity. The Asn291-->Ser mutation of the LPL gene results in reduced lipolytic activity. However, dyslipidemia appears to manifest only if VLDL production is also increased. Hyperinsulinemia was the major determinant of excessive VLDL synthesis and dyslipidemia among the subjects heterozygous for the A291S mutation in this study.