Objectives: To study whether (i) the low-density-lipoprotein (LDL)-receptor gene mutation type itself or (ii) the PvuII restriction-fragment-length polymorphism (RFLP) of the intact LDL-receptor gene affects serum lipid levels and their responses to lovastatin treatment in heterozygous familial hypercholesterolaemia (FH).
Design: Comparison of serum lipid levels in 149 heterozygous FH patients, including 79 patients with the FH Helsinki gene and 70 patients with the FH North Karelia gene, grouped according to the PvuII RFLP status of their nonmutated LDL-receptor allele; studies of lovastatin responses in 23 FH patients with different mutation types.
Subjects: Molecularly defined heterozygous FH patients.
Interventions: DNA analysis by polymerase chain-reaction assay (PCR) and Southern blotting, fasting serum lipid measurements in all patients, and administration of lovastatin 40-80 mg daily to 16 FH Helsinki patients and seven FH North Karelia patients.
Main outcome measures: Baseline and post-treatment serum cholesterol. LDL cholesterol, high-density-lipoprotein (HDL) cholesterol and triglyceride levels.
Results: There were no significant differences in serum total or LDL-cholesterol levels in FH patients with the FH Helsinki gene compared with those carrying the FH North Karelia gene. Regardless of the mutation type, patients without the PvuII site in the normal LDL-receptor gene (P--subjects) tended to have 6-8% higher serum and LDL-cholesterol levels than patients possessing this restriction site (P+ subjects). Although not statistically significant, this difference is qualitatively and quantitatively similar to that reported in three different non-FH populations. Treatment with lovastatin brought about similar hypolipidaemic responses in FH patients with either mutation type (FH Helsinki or FH North Karelia) or PvuII RFLP status (P+ or P-).
Conclusions: Two LDL-receptor gene mutations with dissimilar phenotypic characteristics are associated with similar serum lipid levels and response to statin treatment. Our data also support the previous assumption that the PvuII RFLP of the LDL-receptor gene locus is associated with variation of serum cholesterol levels.