The relationship between molecular defect and clinical phenotype has been examined in 42 patients with heterozygous familial hypercholesterolaemia (FH) and premature
coronary heart disease. The defined defects included mutations in the
low density lipoprotein (
LDL)-receptor gene (23/42) or the
apolipoprotein B Arg3500Gln mutation (5/42). Mean
LDL-cholesterol was higher, both before and during treatment with
simvastatin and
bile acid sequestrants, in patients predicted as having a 'severe' mutation than in those with a 'mild' mutation (8.72 +/- 2.02 mmol/l vs 6.63 +/- 1.8, P = 0.05 before and 4.51 +/- 0.90 mmol/l vs 3.19 +/- 0.58, P = 0.05 during treatment). Maximum inducible
LDL-receptor activity in cultured lymphoblasts was inversely correlated with
LDL-cholesterol before (r2 = 0.499, P = 0.002) and during (r2 = 0.478, P = 0.004) treatment in patients with a defined mutation in the
LDL-receptor gene, but not in the 14 patients with no detectable molecular defect.
LDL-cholesterol concentrations before and during treatment were significantly correlated in patients with a defined
LDL-receptor gene mutation (r2 = 0.548, P = 0.0001), but not in those with no detectable genetic defect. All these correlations were weak, however and there were no differences in the response to treatment in terms of either relative reduction or absolute decrease in
LDL-cholesterol concentration between patients with different
LDL-receptor defects. We conclude that only part of the variable phenotype of heterozygous FH patients is explained by different
LDL-receptor defects and that other factors determine the severity of their hypercholesterolaemia and the onset of
coronary disease.