MUTATIONS AT THE LIPOPROTEIN-LIPASE GENE LOCUS IN SUBJECTS WITH DIABETES-MELLITUS, OBESITY AND LIPEMIA

1. The common association of obesity, diabetes mellitus and hyperlipid aemia may have a primary aetiological basis. Insulin resistance has be en postulated as a possible cause, but defects in the plasma transport of triacylglycerol or fatty acids could also be primary determinants. 2. We have, therefore studied 18 patients with diabetes mellitus, obe sity and severe hypertriglyceridaemia for defects of a key protein inv olved in the clearance of plasma triacylglycerols, lipoprotein lipase. 3. DNA was prepared from leucocytes of 18 patients with the above syn drome, and exons encoding lipoprotein lipase mere amplified by PCR. Th e products were sequenced using the dideoxy chain-termination method. 4. Eight of the subjects were found to possess genetic variants at the lipoprotein lipase gene locus. These were: (a) G(579)--> A, V108V; (b ) G(818)--> A, G188E; (c) C-829--> T, R192; (d) A(1127)--> G, (NS)-S-2 91; (e) C-1308--> G, F351L; (f) C-1338--> A, T361T; and (g) C-1595--> G, S447. Three of these, (c), (e) and (f), have not hitherto been desc ribed. Variant (f), appears to be a population polymorphism whose alle le frequency in normolipidaemic diabetics was found to be 0.12 (162 ch romosomes studied). The others are all rare at frequencies of <0.01 an d may contribute to the phenotype by impairing clearance of plasma tri acylglycerols. 5. We conclude that genetic variants at the lipoprotein lipase locus occur commonly in subjects with this syndrome (four out of 18 subjects with probably functional mutants) and may affect the in dividual's response to obesity and diabetes mellitus for the developme nt of lipaemia.