HETEROZYGOSITY FOR ASN(291)-]SER MUTATION IN THE LIPOPROTEIN-LIPASE GENE IN 2 FINNISH PEDIGREES - EFFECT OF HYPERINSULINEMIA ON THE EXPRESSION OF HYPERTRIGLYCERIDEMIA

We describe two Finnish kindreds with the Asn(291) --> Ser mutation (A 291S) of the lipoprotein lipase (LPL) gene. Sixteen subjects (9 male, 7 female) heterozygous for this mutation were studied and compared wit h 17 unaffected family members or spouses (family controls) and 19 unr elated healthy subjects (population controls). In the group of subject s heterozygous for the A291S mutation, postheparin plasma LPL activity was on average 23% lower than in the family controls and 29% lower th an in the population controls. In agreement, in vitro expression studi es with COS-7 cells showed that the mutant protein exhibits approximat ely 50% of the lipolytic activity of the wild-type protein. Median ser um triglyceride concentration was 2.90 mmol/l in the group of heterozy gotes, 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 lipoprotei ns (LDL) as assessed by gradient gel electrophoresis. Nine of the hete rozygous subjects were hypertriglyceridemic (serum triglyceride concen tration > 2.0 mmol/l). Age or body mass index were not related to the presence of hypertriglyceridemia. By contrast, all hypertriglyceridemi c subjects were either hyperinsulinemic (serum insulin concentration > 10 mU/1, 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 conc entration, the presence of the A291S mutation, serum insulin concentra tion, and postheparin plasma LPL activity. The Asn(291) --> Ser mutati on of the LPL gene results in reduced lipolytic activity. However, dys lipidemia appears to manifest only if VLDL production is also increase d. Hyperinsulinemia was the major determinant of excessive VLDL synthe sis and dyslipidemia among the subjects heterozygous for the A291S mut ation in this study.-Syvanne, M., M. Antikainen, S. Ehnholm, H. Tenkan en, S. Lahdenpera, C. Ehnholm, and M-R. Taskinen. Heterozygosity for A sn(291) --> Ser mutation in the lipoprotein lipase gene in two Finnish pedigrees: effect of hyperinsulinemia on the expression of hypertrigl yceridemia.