REGULATORY MUTATIONS IN THE HUMAN LIPOPROTEIN-LIPASE GENE IN PATIENTSWITH FAMILIAL COMBINED HYPERLIPIDEMIA AND CORONARY-ARTERY DISEASE

We previously reported a compound heterozygote [T(-39)C/T(-93)G] in th e human lipoprotein lipase (LPL) gene promoter in one out of 19 patien ts with familial combined hyperlipidemia (FCHL) and reduced post-hepar in plasma LPL levels. The T(-39)C substitution resulted in 85% decreas e in LPL promoter activity. Further screening of Caucasian patients wi th FCHL, coronary artery disease (CAD), and of unselected Caucasian su bjects revealed four additional LPL promoter variants. Among the same 19 FCHL patients with reduced LPL levels, we found one heterozygote fo r a G(-53)C substitution. Among 115 CAD patients, we found five hetero zygotes and one homozygote for the T(-93)G substitution and one hetero zygote for a CC insertion between +13 and +19 of the 5' untranslated r egion. In a group of 183 unselected subjects, three heterozygotes with the T(-93)G substitution were found. The G(-53)C substitution led to approximately 70-15% decrease in promoter activity as assayed by trans ient transfections of THP-1 (macrophage-like) and C2C12 (myotube-like) cells. The T(-93)G substitution resulted in reduction of promoter act ivity by approximately 40-50%. The CC insertion between +13 and +19 ca used a decrease in promoter activity by 20% in THP-1 and 50% in C2C12. Substitutions at -79 and -95, which had no effect on promoter functio n, were also discovered in the population samples studied. The finding of two promoter mutations (-39 and -53) among 19 FCHL patients with d iminished LPL, but not among the other groups of subjects, suggests a potential role of regulatory mutations of the LPL gene in the developm ent of dyslipidemia in FCHL.