Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: Influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol

The aims of this study were to examine the presence of mutations in the low -density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnos is helps to predict the response to simvastatin treatment in our familial h ypercholesterolemia population. Fifty-five probands and 128 related subject s with familial hypercholesterolemia were studied. Genetic diagnosis was ca rried out following a three-step protocol based on Southern blot and PCR-si ngle strand conformational polymorphism. analysis. A randomized clinical tr ial with simvastatin was conducted in 42 genetically diagnosed subjects wit h familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hyp ercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been pre viously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of p lasma total and low-density lipoprotein cholesterol levels in these subject s were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 3 0.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects wi th defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with famili al hypercholesterolemia with null mutations (P < 0.001). In an outbreed Cau casian population, a three-step protocol for genetic screening detected a m utation in the low-density lipoprotein receptor gene in a high percentage ( 84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma hig h-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment.