Responsável: Mafalda Bourbon
Financiamento e data: Sociedade Portuguesa de Cardiologia (2006-2009).
Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant disorder with a frequency of 1/500 in most of Europe. FH usually results from inherited defects in the Low Density Lipoprotein receptor gene (LDLR) and is characterised by increased circulating LDL cholesterol that leads to lipid accumulation in arteries and tendons (xanthomas) causing premature arteriosclerosis and coronary heart disease (CHD). Mutations in other genes as the apolipoprotein B gene (APOB) and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) are also responsible for FH. Patients with mutations in these genes presents a similar phenotype to patients with mutations in the LDLR gene.
Objectives: The aim of the study is the clinical and molecular characterization of patients with a clinical diagnosis of Familial Hypercholesterolaemia (FH) to allow cascade screening of the relatives of index patients.
Methods: During the duration of the project (3 years) blood samples will be collected from 300 index patients (adults and children) and relatives, approximately a total of 1500 individuals. Amplified fragments of genomic DNA of these 300 index patients will be analysed for mutations in the LDL receptor gene by highly sensitive denaturing high pressure liquid chromatography (DHPLC) and direct sequencing, an optimised method currently under taken at the research lab. The search for large rearrangements in this gene will be done by multi-ligand probe amplification (MLPA). The APOB gene of these 300 index patients will be analysed by amplification and sequencing of a fragment containing the 4 most common APOB mutations. The 12 exons of the PCSK9 of patients without a mutation in the LDLR gene or in the APOB gene will also be amplified and analysed by direct sequencing.
Results: It is expected that 50-60% of the clinical FH patients have a mutation in the LDLR gene or in the APOB gene. About 10% of patients without mutations in the LDLR gene or APOB gene will have a mutation in the PCSK9 gene. Relatives of these patients will be studied to identify other FH patients giving a total number of about 500 newly identified FH patients.
Expected Results: Knowledge of the molecular basis of the disease allows correct diagnosis and appropriate therapeutic measures, since patients with an inherited defect in cholesterol metabolism need more aggressive therapeutic intervention. Genetic diagnosis also allows early identification of relatives at risk, reducing their cardiovascular risk by the administration of cholesterol lowering treatment, which should see their quality of life and life expectancy increased.
Site sobre Hipercolesterolemias Genéticas.