Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. / Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly
caused by defective sarcomeric proteins, is considered a model for studying left
ventricular hypertrophy (LVH) in the absence of increased external loading conditions.
The disease manifests extreme variability in the degree and pattern of LVH, even in
HCM patients with the same causal mutation. The clinical phenotype of HCM can
therefore be viewed as a product of the effect of sarcomere dysfunction and of additional
genetic modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) are
plausible candidate modifiers because of their effect on blood pressure and their direct
hypertrophic effect on cardiomyocytes.
The present study investigated genes encoding components of the RAAS for association
with cardiac hypertrophy traits, in 353 individuals comprised of genetically and
echocardiographically affected and unaffected family members, belonging to 22 HCM
families with HCM founder mutations by employing a multi-SNP approach with TaqMan
allelic discrimination technology. Gene-gene interaction analysis was also performed to
investigate the effect of epistasis on hypertrophy. Candidate genes for analysis included
the angiotensin II type 2 receptor (AT2 receptor), renin, renin-binding protein (RnBP), the
(pro)renin receptor, the mineralocorticoid receptor as well as genes encoding subunits of
the epithelial sodium channels (ENaC) and Na+/K+-ATPase that showed evidence for
cardiac expression.
The present study demonstrates for the first time that variations in the renin and RnBP
genes play a role in modulating hypertrophy in HCM, independent of blood pressure and
confirms the involvement of the AT2 receptor in hypertrophy in HCM. Additionally we
report an association between Na+/K+-ATPase α1- and β1-subunits as well as the ENaC
α- and β-subunits and hypertrophy. Significant evidence for epistasis was found between
renin and downstream RAAS effectors, suggesting a complex interplay between these
RAAS variants and the hypertrophic phenotype in HCM. The identification of such
modifiers for HCM may offer novel targets for hypertrophy research and ultimately antihypertrophic
therapy.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/2667 |
| Date | 03 1900 |
| Creators | Carstens, N. |
| Contributors | Moolman-Smook, J.C., Van der Merwe, L., University of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | University of Stellenbosch |
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