A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

Molecular genetics of familial hypercholesterolemia in Israel.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by a multitude of low density lipoprotein receptor (LDL-R) mutations. The purpose of the current investigation was to define the spectrum of mutations causing FH in Israel and determine their relative distribution among diverse origin groups. A total of 193 FH families were recruited in Israel, 54 of them through the MED PED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDL-R using single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) or both has been completed in 95 index cases. This analysis resulted in the identification of 15 LDL receptor mutations, including 7 novel mutations (del 197, C308G, R385W, splice junction mutation of intron 14, del 328, del 502-505, stop 10, del 165), that were present in 49 index cases (52%). The 15 mutations are mapped to three known functional domains of the receptor (7 in the LDL-binding region, 7 in the epidermal growth factor precursor homology region and 1 in the membrane-spanning region). Screening for the identified mutations in the remaining 98 index cases enabled the molecular diagnosis of 31 additional cases. It is therefore concluded that 80 out of 193 index cases (41%) harbor 1 of the 15 mutations described here. Three mutations-del197 (FH-Lithuania), D147H (FH-Sephardic), and stop660 (Lebanese allele)-were found in a total of 66 index cases (34%); these may be regarded as founder mutations in the three respective origin groups. In conclusion, in Israel molecular heterogeneity at the LDL receptor gene locus reflects the ethnic distribution of its origin groups. The results of the present investigation provide valuable diagnostic tools for a subset of the Israeli patients with FH who are at high risk for atherosclerosis and its complications.

High-dose fluvastatin and bezafibrate combination treatment for heterozygous familial hypercholesterolemia.

This study assessed the long-term use of fluvastatin, alone or in combination with bezafibrate, in patients with severe familial hypercholesterolemia who, in a previous study, did not achieve target levels (European Atherosclerosis Society) of low density lipoprotein cholesterol (LDL-C) with fluvastatin at 60 mg/day plus bezafibrate 200 mg/day, with or without cholestyramine (CME) at 8 g/day. This open-label study comprised 3 periods: period I, 6 weeks of fluvastatin at 40 mg twice daily (at breakfast and at bedtime); period II, fluvastatin at 80 mg/day (40 mg at breakfast, 40 mg at bedtime), and bezafibrate at 200 mg/day (at lunchtime) for 6 weeks in patients not achieving LDL-C target levels; and period III, force-titration of fluvastatin to 800 mg/day (as in period II) and bezafibrate at 400 mg/day (slow release) in patients receiving combination treatment. Patients were excluded if, during the previous study, they had experienced a serious drug-related adverse event or deterioration in liver or kidney function (liver enzymes > 3 times upper limit of normal). The standard physical and laboratory evaluations were performed at regular intervals. Lipid profiles were determined from 12-hour fasting blood samples. All adverse events occurring or worsening during the study, whether spontaneously reported or elicited by questioning, and regardless of relationship to study medication, were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of triple therapy (fluvastatin-bezafibrate-cholestyramine) for severe familial hypercholesterolemia.

Familial hypercholesterolemia carries a markedly increased risk of coronary artery disease. Reduction of plasma low density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors plus resins or fibrates. The current, 60-week, open-label investigation involved 22 patients whose plasma LDL-C had not reached the target level for prevention of coronary artery disease in 3 previous studies using fluvastatin alone and in combination with other cholesterol-lowering medications. At the beginning of the current study, patients were stabilized on fluvastatin monotherapy at 40 mg/day. After 6 weeks, the daily treatment changed to a combination of fluvastatin 40 mg/day in the evening and bezafibrate 400 mg/day in the morning. After a further 6 weeks, a lunchtime dose of cholestyramine 8 g/day was added, to form triple cholesterol-lowering therapy. Efficacy was determined by plasma lipid/lipoprotein analysis. Baseline levels were assessed after 4 weeks of placebo treatment, prior to active treatment, in the first fluvastatin study. Safety analyses included liver and renal function tests, creatine phosphokinase levels and blood counts. Compliance was determined by counting the fluvastatin capsules, bezafibrate tablets, and cholestyramine sachets returned by the patients at each visit. The triple-drug combination used in this study was more effective than the double therapy and resulted in stabilization of the LDL-C:high density lipoprotein cholesterol (HDL-C) ratio, at a reduction from baseline ranging from -40.4 to -52.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combination.

PURPOSE: Familial hypercholesterolemia (FH) carries a markedly increased risk for coronary artery disease (CAD). Reduction of plasma low-density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs. The major objective of this study is to compare two different drug combinations for the treatment of heterozygous FH. PATIENTS AND METHODS: The current investigation is a short-term, double-blind study comparing the efficacy and safety of fluvastatin when combined with cholestyramine (group 1) or with bezafibrate (group 2) in 38 patients with heterozygous FH. RESULTS: After 6 weeks of combination treatment, in comparison to a drug-free baseline (patients receiving single-blind placebo during the lead-in period of an earlier study, ie, before ever receiving fluvastatin), the combination of 40 mg/d of fluvastatin with 400 mg/d of bezafibrate in group 2 reduced plasma LDL-C levels by 35% as compared with 32% in group 1, and reduced the LDL-C/high-density cholesterol (HDL-C) ratio by 46%, compared to 37% in group 1 (a non-significant difference for both comparisons). When compared to an intermittent 6-week open-label administration of 40 mg fluvastatin monotherapy, the addition of cholestyramine or bezafibrate each reduced LDL-C by an additional 13% (P < 0.01 for both regimens). CONCLUSIONS: Fluvastatin-bezafibrate is superior to a fluvastatin-cholestyramine combination for lowering serum triglycerides and elevating HDL-C serum levels in patients in conjunction with a significant lowering of LDL-C/HDL-C ratios, and may be an effective synergistic therapy for heterozygous FH. No episodes of myositis were seen in this short-term study, a finding that is in agreement with most of the reported studies on statin-fibrate combinations reviewed here.

Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia.

BACKGROUND: In familial hypercholesterolemia, plasma lipoproteins can be modulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, although the underlying response mechanisms are still unknown. METHODS AND RESULTS: A single-blind study with fluvastatin, an HMG-CoA reductase inhibitor, was conducted in 64 familial hypercholesterolemia patients who had defined apolipoprotein E (apo E) and apolipoprotein(a) [apo(a)] isoforms. Plasma lipids and lipoproteins were analyzed throughout the study. The patients were grouped according to low density lipoprotein (LDL) receptor genotype. After 4 weeks of treatment with 40 mg of fluvastatin, the mean decrease in plasma LDL cholesterol (LDL-C) in patients with the genetically characterized "Sephardic" and "Lithuanian" mutations was 16-18%, whereas in the other three groups, it was 25-30% (p < 0.005). High density lipoprotein cholesterol (HDL-C) levels increased in all groups. Multivariate analyses suggested that 41% of the LDL-C response can be explained by the LDL receptor mutation, body mass index, apo E3/E4 phenotype, apo(a) isoform LpS2, and baseline LDL-C levels, and 46% of the change in HDL-C is associated with age, sex, body mass index, baseline HDL-C, and the Sephardic mutation. CONCLUSIONS: Fluvastatin exhibits diverse and independent effects on plasma lipoproteins related to several constitutional, genetic, and familial factors. Information regarding these factors may provide better prediction of patients' clinical responses to fluvastatin.

Efficacy and safety of high dose fluvastatin in patients with familial hypercholesterolaemia.

The efficacy and safety of the HMG CoA reductase inhibitor fluvastatin have been evaluated in a double blind study in 52 patients with familial hypercholesterolaemia. A standard AHA Phase II lipid lowering diet was prescribed throughout the study. After 6 weeks of a single blind dosage stabilisation period, in which patients received fluvastatin 40 mg qPM, patients were randomly allocated to one of two double blind treatment groups: group A (n = 24) received fluvastatin 20 mg b.d. for 12 weeks and fluvastatin 20 mg AM + 40 mg PM for an additional 12 weeks; Group B (n = 28) received fluvastatin 40 mg qPM during the entire study. Safety and tolerability were evaluated by the analysis of biochemical and haematological parameters, and ophthalmological and physical examinations. Efficacy was analysed by the determination of plasma lipids, lipoproteins and apoproteins. Fluvastatin 40 mg/d was associated with up to a 27.4% decrease in LDL-C and a 9.6% increase in HDL-C concentrations. Increasing the dose of fluvastatin from 20 mg b.d. to 60 mg per day in Group A was associated with a 7.1% decrease in LDL-C, a 12.1% increase of HDL-C and a 12.8% decrease in the LDL-C/HDL-C ratio. In comparison with Group B (40 mg qPM) LDL-C, HDL-C and the LDL-C/HDL-C ratio in Group A (60 mg) differed by -8.9%, 6.6% and -12%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)