- Rare genetic variants associated with early onset CVD
- Award date
- 3 March 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in Western societies. CVD is mainly triggered by atherosclerosis. A combination of lipid accumulation, inflammation at the vessel wall and thrombotic reactions are underlying its pathobiology. Despite improvements in the therapy of atherosclerotic disease, it is still the leading cause of death in the developed world. The further development of effective therapeutic approaches is needed. This requires better understanding of the molecular mechanisms and pathophysiology of the disease.
We attempted to unravel some of those unknown mechanisms underlying the pathophysiology of atherosclerosis by performing extensive genetic screening in families with a monogenic prevalence of the disease.
We collected patients with early onset CVD at a young age and a familial predisposition for CVD. A combination of classical linkage analysis and next generation sequencing was applied to identify the rare variant that is linked to the early onset CVD phenotype in those families. A rare variant in KERA was identified in a large pedigree with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis. Furthermore a rare functional variant in MCF2L was identified in a small pedigree with premature CVD. The presence of MCF2L in human atherosclerotic plaque specimen lends support to its potential role in atherosclerosis. Based on these data we concluded that KERA and MCF2L might be novel players in the pathological process underlying atherosclerosis.
- Research conducted at: Universiteit van Amsterdam
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