The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia

In a genetically heterogeneous group of 109 patients with a clinical diagno sis of heterozygous familial hypercholesterolaemia (FH), the influence of g ender, apolipoprotein (apo) E genotype and the type of molecular defect in the LDL-receptor (LDLR) gene on the reduction of plasma LDL-cholesterol lev els to treatment with a HMG-CoA reductase inhibitor (simvastatin) were stud ied. Response was determined as the percentage fall in LDL-cholesterol from untreated levels and as the proportion of patients where levels fell below 4.9 or 4.1 mmol/l. Of the patients, 86 individuals had tendon xanthomata ( TX +) and a diagnosis of 'definite' FH and these individuals presented with a significantly higher untreated LDL-cholesterol compared to the 23 indivi duals who did not have xanthomas (TX -) and a diagnosis of 'probable' FH (8 .14 +/- 0.19 vs. 6.81 +/- 0.25, P = 0.001). Overall, HMG-CoA reductase inhi bitor doses of 10, 20 or 40 mg/day resulted in a significant fall of LDL-ch olesterol levels of 29, 39 and 49%, but at all doses those with TX had sign ificantly higher levels than those without, and significantly fewer TX + pa tients achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l than the TX - group (P < 0.05 at each dose). In the TX + group the response to treatmen t was of similar magnitude in men and women and in patients with different apoE genotype. In the 'probable' FH probands only three mutations were iden tified (detection rate 13%), one in the LDLR gene and two in the APOB gene, a detection rate significantly lower (P = 0.02) than in the 'definite' FH probands where 28 mutations were detected (detection rate 37%). In the TX patients where no mutation was detected, treatment resulted in a greater p roportion achieving LDL-cholesterol levels below 4.9 and 4.1 mmol/l compare d to those with any LDLR mutation, this difference was close to statistical significance at the 4.9 mmol/l threshold at 10 mg/day (41 vs. 13%, P = 0.0 58). For the 14 patients with an LDLR mutation that was predicted to be 'se vere', fewer achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l at eac h dosage compared to the 16 individuals with 'mild' mutations, and this dif ference was statistically significant at the maximal dosage of 40 mg/day (P = 0.018). Thus although characterisation of the molecular defect in FH pat ients may not be relevant to their immediate clinical management, those wit h a particular mutation may need more aggressive lipid-lowering treatment t o reach LDL-cholesterol levels recommended to reduce the risk of coronary h eart disease (CHD). (C) 1999 Elsevier Science Ireland Ltd. All rights reser ved.