INFLUENCE OF GENOTYPE AT THE LOW-DENSITY-LIPOPROTEIN (LDL) RECEPTOR GENE LOCUS ON THE CLINICAL PHENOTYPE AND RESPONSE TO LIPID-LOWERING DRUG-THERAPY IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

The relationship between molecular defect and clinical phenotype has b een examined in 42 patients with heterozygous familial hypercholestero laemia (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-c holesterol was higher, both before and during treatment with simvastat in and bile acid sequestrants, in patients predicted as having a 'seve re' 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 act ivity in cultured lymphoblasts was inversely correlated with LDL-chole sterol before (r(2) = 0.499, P = 0.002) and during (r(2) = 0.478, P = 0.004) treatment in patients with a defined mutation in the LDL-recept or gene, but not in the 14 patients with no detectable molecular defec t. LDL-cholesterol concentrations before and during treatment were sig nificantly correlated in patients with a defined LDL-receptor gene mut ation (r(2) = 0.548, P = 0.0001), but not in those with no detectable genetic defect. All these correlations were weak, however and there we re no differences in the response to treatment in terms of either rela tive reduction or absolute decrease in LDL-cholesterol concentration b etween patients with different LDL-receptor defects. We conclude that only part of the variable phenotype of heterozygous FH patients is exp lained by different LDL-receptor defects and that other factors determ ine the severity of their hypercholesterolaemia and the onset of coron ary disease. (C) 1998 Elsevier Science Ireland Ltd.