A FREQUENTLY OCCURRING MUTATION IN THE LIPOPROTEIN-LIPASE GENE (ASN291SER) CONTRIBUTES TO THE EXPRESSION OF FAMILIAL COMBINED HYPERLIPIDEMIA

We performed denaturing gradient gel electrophoresis (DGGE) of exons 4 , 5, 6 and their exon-intron boundaries of the LPL-gene in 169 unrelat ed male patients suffering from familial combined hyperlipidemia (FCH) . Twenty patients were found to carry a nucleotide substitution in exo n 6. Sequence and PCR/ digestion analysis revealed one common mutation (Asn291Ser) in all these cases. This mutation was also present in 215 male controls, albeit at a lower frequency than in FCH patients (10/2 15 = 4.6% vs, 20/169 = 11.8%; p <0.02). Analysis of lipid, lipoprotein and apolipoprotein levels demonstrated an association between the pre sence of this Asn291Ser substitution and decreased HDL-cholesterol (0. 94 +/- 0.31 vs. 1.12 +/- 0.26 mmol/l; p <0.04) in our controls, FCH pa tients carrying this mutation showed decreased HDL-cholesterol (0.75 /- 0.16 vs. 0.95 +/- 0.36 mmol/l; p = 0.05) and increased triglyceride levels (5.96 a 4.12 vs. 3.48 +/- 1.78 mmol/l; p <0.005) compared to n on-carriers. The high triglyceride and low HDL-cholesterol phenotype i n carriers of this substitution was most obvious when BMI exceeded 27 kg/m(2). Our study of male FCH patients revealed the presence of a com mon mutation in the LPL-gene that is associated with lipoprotein abnor malities, indicating that defective LPL is at least one of the factors contributing to the FCH-phenotype.