Mutations of the human hepatic lipase gene in patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in patients with familial combined hyperlipidemia

Hepatic lipase is an enzyme which hydrolyzes triglycerides from plasma lipo proteins and thus takes part in the metabolism of intermediate density lipo proteins and high-density lipoproteins. The search described here concentra ted on mutations of the HL gene in 129 patients with combined hypertriglyce ridemia/hyperalphalipoproteinemia and in 184 members of 19 families with fa milial combined hyperlipidemia. Controls were 100 subjects with favorable l ipid values (age 46-51 years). Mutation screening and analysis were perform ed by temperature-gradient gel electrophoresis, allele-specific restriction ,genotyping, and sequencing. Six different missense mutations and four diff erent silent mutations were found in the HL gene. The alleles Phe-267 and G ln-343 were detected only once in the patient group with hypertriglyceridem ia and hyperalphalipoproteinemia and were not detected in the control group . The allele Met-383 was rare in both patients and controls. We found 9.3% of the patients and only 3.0% of controls to be carrying the Val-73-Met mis sense mutation. The allele Phe-334 was found in 5.43% of patients and in 2. 0% of controls. The difference between the frequencies of these alleles was significant between male patients and male controls (Met-73 P=0.044; Phe-3 34 P=0.047). Also, the summarized odds ratio of 3.28 (95% confidence interv al 1.23-8.73) demonstrates that mutation carriers are significantly more pr evalent in the patients. Fifteen carriers of the Met-73 allele were found i n six families of the familial combined hyperlipidemia group. Furthermore, six carriers of the Phe-334 allele were found in three families of the same group. In comparison to the controls the summarized odds ratio of 2.45 (95 % confidence interval 0.89-6.71) barely missed the level of significance. T he linkage between genotype and phenotype was incomplete. These results sho w an association of the missense mutations Val-73-Met and Leu-334-Phe as su sceptibility alleles for combined forms of hyperlipidemia.