RESUMEN
Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.1187-2A>G) in LDLR. The mutation co-segregated with FH in the family, providing strong genetic evidence to support its pathogenicity. The proband was a 48-year-old male FH patient who had an acute myocardial infarction (MI) and ventricular fibrillation (VF), and showed LDL-C of 5.23 mmol/L. A combination of life style modifications on food and exercise and treatment with rosuvastatin reduced his LDL-C to 2.05-2.80 mmol/L. Addition of ezetimibe did not improve rosuvastatin therapy, but addition of evolocumab further reduced LDL-C by 70% to 0.7 mmol/L at the first time and by 67% to 1.31 mmol/L at the second time. Rosuvastatin also reduced LDL-C for proband's father and sister by 40% and 43-63%, respectively. Lovastatin alone or addition to rosuvastatin treatment did not have any effect on LDL-C for the proband and his son. Both patients carry ApoE 3/4 genotype and SLCO1B1 rs4149056 TT genotype. These results suggest that combined treatment with rosuvastatin (but not lovastatin or ezetimibe) and evolocumab can control LDL-C to meet the LDL-C treatment goal for patients with LDLR splicing mutation c.1187-2A>G.
Asunto(s)
Hiperlipidemias , Hiperlipoproteinemia Tipo II , Anticuerpos Monoclonales Humanizados , LDL-Colesterol/genética , Ezetimiba/uso terapéutico , Humanos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana Edad , Mutación , Linaje , Fenotipo , Proproteína Convertasa 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Rosuvastatina Cálcica/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the effect of the sera of rabbits fed with Tongxinluo on the expression and secretion of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in U937 monocyte-derived macrophages. METHODS: Atherosclerosis was induced in rabbits by high-cholesterol feeding, and the serum was obtained from the rabbits after administration of the aqueous solution of Tongxinluo or simvastatin by gavage. U937 monocyte-derived macrophages were incubated with the sera at different concentrations for 24 hours, and the changes in MMP-9 and TIMP-1 gene expression and secretion were detected by RT-PCR and enzyme-linked immunosorbent assay, respectively. RESULTS: The serum of rabbits fed with Tongxinluo concentration-dependently inhibited the expression and secretion of MMP-9 in U937 macrophages, but did not affect TIMP-1 expression or secretion. CONCLUSION: Tongxinluo may stabilize the atherosclerotic plaques by inhibiting the expression and secretion of MMP-9.
