15289-s-bos

1 9 | Introduction Introduction Familial Hypercholesterolemia (FH) (OMIM #143890) is the most common metabolic disorder with a prevalence estimated between in 1:244 and 1:600 (1-3). FH is associated with premature cardiovascular disease (CVD) (4). FH can be diagnosed by clinical criteria (table 1) and genetically by identification of a pathogenic mutation in the LDLR gene, APOB gene or PCSK9 gene (5-8). Currently over 1200 different mutations are known, most often found in the LDLR gene (www. jojogenetics.nl ). Severity can differ depending on the type of mutation. In general apoB mutations are considered to cause a milder phenotype than LDLR or PCSK9 mutations. Within LDLR mutation, null-mutations, mutations which lead to no residual function of the LDL-receptor, are associated with a more severe phenotype with higher high low- density lipoprotein cholesterol (LDL-C) levels compared to LDLR defective mutations with residual LDL-receptor function (9). The increased LDL-C levels are the driving force of the increased cardiovascular risk in FH patients. To lower CVD risk in FH patients cholesterol lowering agents, mainly statins, are used. The impact of statins on the life expectancy of FH patients can hardly be overestimated. Before the statin era half of men with FH and 12% of women with FH suffered from a myocardial infarction before the age of fifty years (10). However, despite statin therapy some FH patients still develop CVD (11). The classical risk factors: age, male sex, body mass index (BMI), hypertension, diabetes mellitus, smoking and reduces high-density lipoprotein (HDL) levels all clearly contribute to CVD risk in FH patients (12-14). But even in the absence of these classical risk factors some FH patients will develop cardiovascular events. Since every patient who is diagnosed with FH immediately starts on statin treatment, more studies were necessary to determine CVD risk in these treated patients. The aim of this thesis was to identify which of these statin treated FH patients were at a higher risk of developing CVD. To investigate this risk I used different approaches as elaborated below.