Elsevier

Atherosclerosis

Volume 160, Issue 2, February 2002, Pages 361-368
Atherosclerosis

Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia

https://doi.org/10.1016/S0021-9150(01)00584-6Get rights and content

Abstract

The efficacy of the inhibitors of HMG CoA reductase shows considerable interindividual variation and intense research has focused in the recent years to identify the genetic loci and environmental factors responsible for this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG CoA reductase inhibitor, was conducted in 63 adolescents (47 treated versus 17 controls) with heterozygous FH. The patients were grouped according to known low-density lipoprotein (LDL) receptor gene mutation class. After 6 weeks of treatment with 20 mg/d of simvastatin, the mean reduction in plasma LDL-cholesterol in patients with a receptor-negative mutation (n=33) was 39% whereas, in the receptor-defective mutation group (n=14), it was 31% (P=0.01). Multiple regression analyses showed that there was a significant association between the apo E polymorphism and LDL-cholesterol response to simvastatin only among heterozygotes for a receptor-negative mutation. In subjects carrying a receptor-defective mutation, however, we observed that 51% of the variability in LDL-cholesterol response was explained by variations in the dosage of simvastatin expressed in mg/kg/day (P=0.0028). There was no significant association between LDL-cholesterol response and the dosage of simvastatin among heterozygotes for a receptor-negative mutation. The results of the present study have shown that the contribution of apo E polymorphism and the dosage of simvastatin to the LDL-cholesterol responsiveness is influenced by the nature of the LDL receptor gene mutation.

Introduction

Familial hypercholesterolemia (FH), one of the most common inherited disorder, is caused by mutations in the low density lipoprotein (LDL) receptor gene [1]. FH has a co-dominant mode of inheritance with heterozygotes characterized by raised plasma LDL-cholesterol concentrations, tendinous xanthomatosis and premature atherosclerotic coronary heart disease (CHD) usually occurring between the ages of 35 and 55 years. Homozygous or compound heterozygous patients show a 6- to 8-fold increase in plasma LDL-cholesterol concentrations and present manifestations of CHD before the age of 20 years. The worldwide frequency of FH is 1 in 500 for heterozygotes and one per million for homozygotes. In French–Canadians and some other populations such as Christian Lebanese [2], Afrikaners [3], Ashkenazi Jews [4], Finns [5] and Tunisians [6], the prevalence of FH is high as a result of founder effects [7]. Eleven mutations in the LDL receptor gene are responsible for >90% of French–Canadian heterozygous FH patients, defined on the basis of clinical and biochemical criteria [8], [9], [10]. The three most common mutations are, a deletion>15 kb (Δ>15 kb) at the 5′ end of the gene and two missense mutations in exon 3 (W66G) and exon 14 (C646Y), respectively [11]. Taken together, these mutations account for nearly 80% of heterozygous FH patients who attend our lipid clinic in Québec City. The Δ>15 kb is a class I (receptor-negative) mutation and fails to produce immunoprecipitable LDL receptor protein [12], [13]. The C646Y mutation causes the mutant receptor to be rapidly degraded (class IIA, receptor-negative) and results in very low receptor activity (<2% of normal receptor activity), while the W66G mutation exhibits decreased affinity for lipoprotein ligands (class III, receptor-defective) and expresses ∼25% of normal receptor activity [13].

The impact of these mutations on the LDL receptor function has been characterized by considerable variability. In this regard, we have previously shown that the elevation in plasma total and LDL-cholesterol levels is more severe among carriers of a receptor-negative mutation than among subjects with a binding-defective mutation [14], [15]. Accordingly, in two studies conducted in homozygotes and in heterozygotes, respectively, CHD was premature and more severe among carriers of a receptor-negative mutation compared to binding-defective alleles [16].

We have previously reported in a group of heterozygous FH adolescents that 42% of the variation of LDL-cholesterol response to simvastatin is attributable to the LDL receptor and apo E genotypes, and body mass index (BMI) [17]. Simvastatin is a potent inhibitor of 3-hydroxy-3 methylglutaryl coenzyme A (HMG CoA) reductase. In order to further explore the potential underlying mechanisms of response to HMG CoA reductase in FH, the present study was designed to compare the pattern of responsiveness of the plasma total and LDL-cholesterol to simvastatin within two groups of heterozygous FH adolescents carrying distinct functional LDL receptor mutations (receptor-negative versus receptor-defective).

Section snippets

Patients

From a total of 63 heterozygous FH patients aged 8–17 and weighing 27 kg or more who participated in a randomized, double-blind, placebo-controlled clinical trial on the effect of simvastatin, we selected, on the basis of the LDL receptor type mutation, 47 heterozygous subjects that received the simvastatin at the time of the study conducted at the Laval University Lipid Research Clinic in Québec City, Canada. Among them, 33 were carrier of a receptor-negative mutation (20 carriers of the Δ>15

Patient characteristics

A total of 47 French–Canadian adolescents with heterozygous FH (28 boys and 19 girls) with either a receptor-negative or a receptor-defective LDL receptor gene mutation were selected to participate in this study. Table 1 shows the characteristics of the two LDL receptor functional groups. The two groups were comparable for age, smoking habits, and the male–female ratio. The prevalence of the apo E alleles was also similar in the two groups. Although not significant, a trend toward higher plasma

Discussion

The results of the present study provide new clinically relevant information regarding the genetic determinants modulating patients’ responses to simvastatin and the potential underlying mechanisms. The three LDL receptor gene mutations studied alter the LDL receptor function differently. In two of these mutations (Δ>15 kb, C646Y), the LDL receptor protein is completely absent from the cell surface (receptor-negative). The Δ>15 kb impairs the production of mRNA due to deletion of the promoter

Acknowledgements

We are indebted to Nicole Roy, RN (Centre Hospitalier de l'Université Laval) for coordinating the study; Odette Navratil, RD, for dietary consultations; Sophia Papas, Ph.D., (Merck Frosst Canada) for monitoring the study and Daniel Morissette, M.Sc., MFCI, for statistical consultation. We are also indebted to the patients and their parents involved in this study. Marie-Claude Vohl and Jean Bergeron received a scholarship from the Fonds de la Recherche en Santé du Québec and Patrick Couture is

References (37)

  • J. O'Malley et al.

    The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia

    Metabolism

    (1990)
  • C. Sanllehy et al.

    Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia

    Metabolism

    (1998)
  • Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors....
  • M.J. Kotze et al.

    An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics

    J. Med. Genet.

    (1990)
  • H.C. Seftel et al.

    Prevalence of familial hypercholesterolemia on Johannesburg Jews

    Am. J. Med. Genet.

    (1989)
  • K. Aalto-Setala et al.

    Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland

    J. Intern. Med.

    (1992)
  • S. Moorjani et al.

    Homozygous familial hypercholesterolemia among French–Canadians in Quebec Province

    Arteriosclerosis

    (1989)
  • J. Simard et al.

    Detection of a novel mutation (stop468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French–Canadians

    Hum. Mol. Genet.

    (1994)
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