Background: With the increasing number of FH patients identified in the general population by the national FH case-finding program, executed by the StOEH ("Stichting Opsporing Erfelijke Hypercholesterolemie") and supported by the Dutch government, it becomes evident that a significant proportion of identified carriers of LDL-receptor gene mutations has normal or moderately elevated LDL-cholesterol levels.
Hypothesis: It is generally accepted that FH is a fully penetrant autosomal dominant disorder, but closer examination of a large non-lipid clinical cohort of FH patients suggests that this is not the case. The cause of lower than expected LDL-cholesterol levels in carriers of LDL-receptor gene mutations is not known, but a number of explanations, genetic and environmental, can underlie this phenomenon. Moreover, the consequences of lower than expected LDL-cholesterol levels for the atherosclerotic process and the effects on the development of cardiovascular disease are unknown.
Study objectives: To determine the cause for and to assess the consequences for the atherosclerotic process of lower than expected LDL-cholesterol levels in carriers of LDL-receotor gene mutations.
Methods: 1. Assess large pedigrees constructed by the StOEH which contain mutation carriers with normal or moderately elevated LDL-cholesterol levels. 2. Contact patients, their treating physicians and, where necessary, unaffected spouses, for additional blood sampling and collecting objective clinical, lipid, life style and dietary data. Confirm that the normal or moderately elevated LDL-cholesterol levels persist overtime. 3. Analyse DNA samples for variants in the genes, known to lower LDL-cholesterol levels, such as apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP). 4. If indicated, perform genetic linkage in pedigrees of interest in order to identify loci associated with lower than expected cholesterol levels. 5. Compose groups of carriers with normal and high cholesterol levels, and healthy controls, matched for age, sex, smoking habits, body mass index and blood pressure. Perform measurements of the intima media complex in these 3 groups.
Expected results: Normal or near-normal LDL-cholesterol levels in FH patients may be a co-inherited trait caused by variations in specific genes, or by a gene yet to be identified. Also environmental factors may underlie the normal or moderately elevated LDL-cholesterol levels observed. Defective LDL-receptors, not resulting in severe hypercholesterolemia, may still enhance the atherosclerotic process through local interactions with the endothelium, as assessed by IMT measurements. |
