- Author
-
L.F. Reeskamp
- Title
- Familial hypercholesterolemia
- Subtitle
- Closing the loop between molecular genetics and personalized medicine
- Supervisors
- Co-supervisors
-
A Grefhorst
- Award date
- 18 June 2021
- Number of pages
- 397
- ISBN
- 9789464165913
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Familial Hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol levels and an increased risk for premature cardiovascular disease.
Part I A and B focus on the diagnostic yield of genetic testing for FH causing variant in patients with clinical FH in The Netherlands and on novel genetic causes of FH in those patients without a known FH causing genetic variant. It is shown that intronic variants in the LDLR gene can cause FH, in contrast to the previously reported FH gene STAP1. Moreover, it appears that rare variants in the genes ABCG5 and ABCG8, and differentially methylated DNA are associated with hypercholesterolemia, but are unlikely to cause FH.
Part II of this thesis focusses on the role of angiopoietin-like 3 (ANGPTL3) protein in regulating lipid metabolism and as a potentially therapeutic target in dyslipidemia. It is shown that inhibition of ANGPTL3 leads to an accelerated clearance of intermediate-density lipoprotein and LDL from the circulation, a meaningful reduction of LDL-C levels in a randomized controlled trial with homozygous FH patients, and atherosclerotic plaque regression in two young homozygous FH patients.
In part III, two other mechanisms of LDL-C lowering are described: the results of a RCT investigating apolipoprotein B oligonucleotide antisense therapy in FH patients are reported and the mechanism by which trans intestinal cholesterol excretion can lead to lower cholesterol levels is reviewed. - Persistent Identifier
- https://hdl.handle.net/11245.1/06607341-241d-4964-b9e1-50b8952aebd3
- Downloads
- Supplementary materials
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