SIMILAR RESPONSE TO SIMVASTATIN IN PATIENTS HETEROZYGOUS FOR FAMILIALHYPERCHOLESTEROLEMIA WITH MESSENGER-RNA NEGATIVE AND MESSENGER-RNA POSITIVE MUTATIONS

In patients heterozygous for familial hypercholesterolemia, the low-de nsity lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-be ta-methylglutaryl coenzyme A reductase inhibitors may depend on the na ture of the mutation in the LDL receptor gene. To test this hypothesis , we compared the response to simvastatin, 20 mg daily for 9 weeks, be tween heterozygous carriers of functionally different classes of mutat ions, i.e. mRNA negative or mRNA positive mutations. Out of 116 consec utive, unrelated patients with familial hypercholesterolemia, 27 patie nts were selected for molecular analyses: 14 patients with mRNA negati ve and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholest erol, lower levels of high-density lipoprotein (HDL) cholesterol and s ignificantly more often tendon xanthomas, compared to patients with mR NA positive mutations. Simvastatin reduced the mean fasting LDL choles terol levels to a similar percentage in the mRNA negative and mRNA pos itive 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%, respe ctively, 95% CI of difference 8-25%, P = 0.002) independent of the res ponse of total triglycerides to simvastatin. The percentage LDL choles terol lowering response varied among multiple carriers of the same mut ation, even in the case of mRNA negative mutations. We conclude that t he percentage LDL lowering response to simvastatin treatment was simil ar in patients with mRNA negative and mRNA positive mutations. Moreove r, variation of this response within multiple carriers of the same mut ation suggests an influence of additional factors. (C) 1998 Elsevier S cience Ireland Ltd.