The role of renin-angiotensin-aldosterone system (RAAS) genes in the development of hypertrophy in hypertrophic cardiomyopathy (HCM)

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dc.contributor.advisorMoolman-Smook, J. C.en_ZA
dc.contributor.advisorVan der Merwe, L.en_ZA
dc.contributor.authorCarstens, N.en_ZA
dc.contributor.otherUniversity of Stellenbosch. Faculty of Health Sciences. Dept. of Biomedical Sciences. Molecular Biology and Human Genetics.
dc.date.accessioned2009-02-24T09:44:56Zen_ZA
dc.date.accessioned2010-06-01T08:54:49Z
dc.date.available2009-02-24T09:44:56Zen_ZA
dc.date.available2010-06-01T08:54:49Z
dc.date.issued2009-03en_ZA
dc.descriptionThesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009.en_ZA
dc.description.abstractHypertrophic 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.en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/2667
dc.language.isoenen_ZA
dc.publisherStellenbosch : University of Stellenbosch
dc.rights.holderUniversity of Stellenbosch
dc.subjectModifiersen_ZA
dc.subjectRenin-angiotensin-aldosterone systemen_ZA
dc.subjectHypertrophic cardiomyopathyen_ZA
dc.subjectHeart hyperthrophy therapyen_ZA
dc.subjectDissertations -- Medicineen_ZA
dc.subjectTheses -- Medicineen_ZA
dc.subject.otherBiomedical Sciencesen_ZA
dc.subject.otherMolecular Biology and Human Geneticsen_ZA
dc.titleThe role of renin-angiotensin-aldosterone system (RAAS) genes in the development of hypertrophy in hypertrophic cardiomyopathy (HCM)en_ZA
dc.typeThesisen_ZA
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