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Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations

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Author: Sijbrands, E.J.G. · Lombardi, M.P. · Westendorp, R.G.J. · Gevers Leuven, J.A. · Meinders, A.E. · Laarse, A. van der · Frants, R.R. · Havekes, L.M. · Smelt, A.H.M.
Institution: Gaubius Instituut TNO
Source:Atherosclerosis, 2, 136, 247-254
Identifier: 234354
doi: DOI:10.1016/S0021-9150(97)00216-5
Keywords: Health · Familial hypercholesterolemia · LDL receptor gene · Simvastatin · Xanthomas · Anticholesteremic Agents · Cholesterol, HDL · Cholesterol, LDL · Female · Heterozygote · Humans · Hyperlipoproteinemia Type II · Male · Middle Aged · Mutation · Receptors, LDL · RNA, Messenger · Simvastatin


In patients heterozygous for familial hypercholesterolemia, the low- density lipoprotein (LDL) cholesterol lowering effect of β-hydroxy-β- methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference - 8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95% CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.