Advertisement

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

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic Basis of Inherited Diseases. New York: McGraw-Hill, 1995. p. 1981–2030.

        • Lehrman M.A.
        • Schneider W.J.
        • Brown M.S.
        • Davis C.G.
        • Elhammer A.
        • Russell D.W.
        • Goldstein J.L.
        The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum.
        J. Biol. Chem. 1987; 262: 401-410
        • Kotze M.J.
        • Warnich L.
        • Langenhoven E.
        • du Plessis L.
        • Retief A.E.
        An exon 4 mutation identified in the majority of South African familial hypercholesterolaemics.
        J. Med. Genet. 1990; 27: 298-302
        • Seftel H.C.
        • Baker S.G.
        • Jenkins T.
        • Mendelsohn D.
        Prevalence of familial hypercholesterolemia on Johannesburg Jews.
        Am. J. Med. Genet. 1989; 34: 545-547
        • Aalto-Setala K.
        • Koivisto U.M.
        • Miettinen T.A.
        • Gylling H.
        • Kesaniemi Y.A.
        • Savolainen M.
        • Pyorala K.
        • Ebeling T.
        • Mononen I.
        • Turtola H.
        • Viikari J.
        • Kontula K.
        Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland.
        J. Intern. Med. 1992; 231: 227-234
        • Slimane M.N.
        • Pousse H.
        • Maatoug F.
        • Hammami M.
        • Ben Farhat M.H.
        Phenotypic expression of familial hypercholesterolaemia in central and southern Tunisia.
        Atherosclerosis. 1993; 104: 153-158
        • Moorjani S.
        • Roy M.
        • Gagné C.
        • Davignon J.
        • Brun D.
        • Toussaint M.
        • Lambert M.
        • Campeau L.
        • Blaichman S.
        • Lupien P.
        Homozygous familial hypercholesterolemia among French–Canadians in Quebec Province.
        Arteriosclerosis. 1989; 9: 211-216
        • Simard J.
        • Moorjani S.
        • Vohl M.C.
        • Couture P.
        • Torres A.L.
        • Gagné C.
        • Després J.P.
        • Labrie F.
        • Lupien P.J.
        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; 3: 1689-1691
        • Couture P.
        • Vohl M.C.
        • Gagné C.
        • Gaudet D.
        • Torres A.L.
        • Lupien P.J.
        • Després J.P.
        • Labrie F.
        • Simard J.
        • Moorjani S.
        Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French–Canadians.
        Hum. Mutat. 1998; 1: S226-S231
        • Assouline L.
        • Leitersdorf E.
        • Lambert M.
        • Reshef A.
        • Feoli-Fonseca J.C.
        • Levy E.
        Identification of two novel LDL receptor gene defects in French–Canadian pediatric population: mutational analysis and biochemical studies.
        Hum. Mutat. 1997; 9: 555-562
        • Vohl M.C.
        • Moorjani S.
        • Roy M.
        • Gaudet D.
        • Torres A.L.
        • Minnich A.
        • Gagné C.
        • Tremblay G.
        • Lambert M.
        • Bergeron J.
        • Couture P.
        • Perron P.
        • Blaichman S.
        • Brun L.D.
        • Davignon J.
        • Lupien P.J.
        • Després J.P.
        Geographic distribution of French–Canadian low-density lipoprotein receptor gene mutations in the Province of Quebec.
        Clin. Genet. 1997; 52: 1-6
        • Hobbs H.H.
        • Brown M.S.
        • Russell D.W.
        • Davignon J.
        • Goldstein J.L.
        Deletion in the gene for the low-density-lipoprotein receptor in a majority of French–Canadians with familial hypercholesterolemia.
        N. Engl. J. Med. 1987; 317: 734-737
        • Hobbs H.H.
        • Brown M.S.
        • Goldstein J.L.
        Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.
        Hum. Mutat. 1992; 1: 445-466
        • Moorjani S.
        • Roy M.
        • Torres A.
        • Bétard C.
        • Gagné C.
        • Lambert M.
        • Brun D.
        • Davignon J.
        • Lupien P.
        Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia.
        Lancet. 1993; 341: 1303-1306
        • Torres A.L.
        • Moorjani S.
        • Vohl M.C.
        • Gagné C.
        • Lamarche B.
        • Brun L.D.
        • Lupien P.
        • Després J.P.
        Heterozygous familial hypercholesterolemia in children-low-density-lipoprotein receptor mutational analysis and variation in the expression of plasma lipoprotein-lipid concentrations.
        Atherosclerosis. 1996; 126: 163-171
        • Vohl M.C.
        • Gaudet D.
        • Moorjani S.
        • Tremblay G.
        • Perron P.
        • Gagné C.
        • Lesiege D.
        • Bergeron J.
        • Lupien P.J.
        • Després J.P.
        Comparison of the effect of two low-density lipoprotein receptor class mutations on coronary heart disease among French–Canadian patients heterozygous for familial hypercholesterolaemia.
        Eur. J. Clin. Invest. 1997; 27: 366-373
        • Couture P.
        • Brun L.D.
        • Szots F.
        • Lelièvre M.
        • Gaudet D.
        • Després J.P.
        • Simard J.
        • Lupien P.J.
        • Gagné C.
        Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French–Canadians with heterozygous familial hypercholesterolemia.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1007-1012
        • Heiss G.
        • Tamir I.
        • Davis C.E.
        • Tyroler H.A.
        • Rifkand B.M.
        • Schonfeld G.
        • Jacobs D.
        • Frantz Jr., I.D.
        Lipoprotein-cholesterol distributions in selected North American populations: the lipid research clinics program prevalence study.
        Circulation. 1980; 61: 302-315
        • Moorjani S.
        • Dupont A.
        • Labrie F.
        • Lupien P.J.
        • Brun D.
        • Gagné C.
        • Giguere M.
        • Bélanger A.
        Increase in plasma high-density lipoprotein concentration following complete androgen blockage in men with prostatic carcinoma.
        Metabolism. 1987; 36: 244-250
        • Albers J.J.
        • Warnick G.R.
        • Wiebe D.
        • King P.
        • Steiner P.
        • Smith L.
        • Breckenridge C.
        • Chow A.
        • Kuba K.
        • Weidman S.
        • Arnett H.
        • Wood P.
        • Shlagenhaft A.
        Multi-laboratory comparison of three heparin-Mn2+ precipitation procedures for estimating cholesterol in high-density lipoprotein.
        Clin. Chem. 1978; 24: 853-856
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin. Chem. 1972; 18: 499-502
        • Laurell C.B.
        Electroimmuno assay.
        Scand. J. Clin. Lab. Invest. 1972; 124: 21-37
        • Ma Y.H.
        • Bétard C.
        • Roy M.
        • Davignon J.
        • Kessling A.M.
        Identification of a second ‘French–Canadian’ LDL receptor gene deletion and development of a rapid method to detect both deletions.
        Clin. Genet. 1989; 36: 219-228
        • Leitersdorf E.
        • Tobin E.J.
        • Davignon J.
        • Hobbs H.H.
        Common low-density lipoprotein receptor mutations in the French–Canadian population.
        J. Clin. Invest. 1990; 85: 1014-1023
        • Vohl M.
        • Couture P.
        • Moorjani S.
        • Torres A.
        • Gagné C.
        • Després J.
        • Lupien P.
        • Labrie F.
        • Simard J.
        Rapid restriction fragment analysis for screening four point mutations of the low-density lipoprotein receptor gene in French–Canadians.
        Hum. Mutat. 1995; 6: 243-246
        • Hixson J.E.
        • Vernier D.T.
        Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.
        J. Lipid Res. 1990; 31: 545-548
        • Gaudet D.
        • Vohl M.C.
        • Couture P.
        • Moorjani S.
        • Tremblay G.
        • Perron P.
        • Gagné C.
        • Després J.P.
        Contribution of receptor negative versus receptor defective mutations in the LDL-receptor gene to angiographically assessed coronary artery disease among young (25–49 years) versus middle-aged (50–64 years) men.
        Atherosclerosis. 1999; 143: 153-161
        • Leitersdorf E.
        • Eisenberg S.
        • Eliav O.
        • Friedlander Y.
        • Berkman N.
        • Dann E.J.
        • Landsberger D.
        • Sehayek E.
        • Meiner V.
        • Wurm M.
        • Bard J.-M.
        • Fruchart J.-C.
        • Stein Y.
        Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia.
        Circulation. 1993; 87: 35-44
        • Carmena R.
        • Roederer G.
        • Mailloux H.
        • Lussier C.S.
        • Davignon J.
        The response to lovastatin treatment in patients with heterozygous familial hypercholesterolemia is modulated by apolipoprotein E polymorphism.
        Metabolism. 1993; 42: 895-901
        • Jeenah M.
        • September W.
        • Graadt R.F.
        • de V.W.
        • Seftel H.
        • Marais D.
        Influence of specific mutations at the LDL-receptor gene locus on the response to simvastatin therapy in Afrikaner patients with heterozygous familial hypercholesterolaemia.
        Atherosclerosis. 1993; 98: 51-58
        • Bétard C.
        • Kessling A.M.
        • Roy M.
        • Chamberland A.
        • Lussier-Cacan S.
        • Davignon J.
        Molecular genetic evidence for a founder effect in familial hypercholesterolemia among French–Canadians.
        Hum. Genet. 1992; 88: 529-536
        • Ordovas J.
        • Lopez-Miranda J.
        • Perez-Jimenez F.
        • Rodriguez C.
        • Park J.
        • Cole T.
        • Schaefer E.
        Effect of apolipoprotein E and A-IV phenotypes on the low density lipoprotein response to HMG CoA reductase inhibitor therapy.
        Atherosclerosis. 1995; 113: 157-166
        • Gregg R.
        • Zech L.
        • Schaefer E.
        • Stark D.
        • Wilson D.
        • Brewer H.J.
        Abnormal in vivo metabolism of apolipoprotein E4 in humans.
        J. Clin. Invest. 1986; 78: 815-821
        • O'Malley J.
        • Illingworth D.
        The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia.
        Metabolism. 1990; 39: 150-154
        • De Knijff P.
        • Stalenhoef A.F.
        • Mol M.J.
        • Gevers Leuven J.A.
        • Smit J.
        • Erkelens D.W.
        • Schouten J.
        • Frants R.R.
        • Havekes L.M.
        Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia.
        Atherosclerosis. 1990; 83: 89-97
        • Ojala J.
        • Helve E.
        • Ehnholm C.
        • Aalto-Setala K.
        • Kontula K.
        • Tikkanen M.
        Effect of apolipoprotein E polymorphism and XbaI polymorphism of apolipoprotein B on response to lovastatin treatment in familial and non-familial hypercholesterolaemia.
        J. Intern. Med. 1991; 230: 397-405
        • Sanllehy C.
        • Casals E.
        • Rodriguez-Villar C.
        • Zambon D.
        • Ojuel J.
        • Ballesta A.M.
        • Ros E.
        Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia.
        Metabolism. 1998; 47: 560-565