Thesis (MScMed)--Stellenbosch University, 2008. / ENGLISH ABSTRACT: In hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder, hypertrophy is variable
within and between families carrying the same causal mutation, suggesting a role for modifier genes.
Associations between left ventricular hypertrophy and left ventricular pressure overload suggested
that sequence variants in genes involved in the Renin-Angiotensin Aldosterone System (RAAS) may
act as hypertrophy modifiers in HCM, but some of these studies may have been confounded by,
amongst other things, lack of adjustment for hypertrophy covariates.
To investigate this hypothesis, twenty one polymorphic loci spread across six genes (ACE1, AGT,
AGTR1, CYP11B2, CMA and ACE2) of the RAAS were genotyped in 353 subjects from 22 South
African HCM-families, in which founder mutations segregate. Genotypes were compared to 17
echocardiographically-derived hypertrophic indices of left ventricular wall thickness at 16 segments
covering three longitudinal levels. Family-based association was performed by quantitative
transmission disequilibrium testing (QTDT), and mixed effects models to analyse the X-linked gene
ACE2, with concurrent adjustment for hypertrophy covariates (age, sex, systolic blood pressure (BP),
diastolic BP, body surface area, heart rate and mutation status).
Strong evidence of linkage in the absence of association was detected between polymorphisms at
ACE1 and posterior and anterior wall thickness (PW and AW, respectively) at the papillary muscle
level (pap) and apex level (apx). In single-locus analysis, statistically significant associations were
generated between the CYP11B2 rs3097 polymorphism and PW at the mitral valve level (mit) and
both PWpap and inferior wall thickness (IW)pap. Statistically significant associations were
generated at three AGTR1 polymorphisms, namely, between rs2640539 and AWmit, rs 3772627 and
anterior interventricular septum thickness at pap and rs5182 and both IWpap and AWapx.
Furthermore, mixed effects model detected statistically significant association between the ACE2
rs879922 polymorphism and both posterior interventricular septum thickness and lateral wall
thickness at mit in females only.
These data indicate a role for RAAS gene variants, independent of hypertrophy covariates, in
modifying the phenotypic expression of hypertrophy in HCM-affected individuals. / AFRIKAANSE OPSOMMING: Hipertrofiese kardiomiopatie (HCM), ‘n autosomale dominante afwyking, toon hoogs variërende
hipertrofie binne en tussen families wat dieselfde siekte-veroorsakende mutasie het, hierdie dui op
die moontlike betrokkenheid van geassosieerde modifiserende gene. Assosiasies tussen linker
ventrikulêre hipertrofie en linker ventrikulêre druk-oorlading stel voor dat volgorde variasies in gene
betrokke in die Renin-Angiotensin Aldosteroon Sisteem (RAAS) mag optree as hipertrofie
modifiseerders in HCM. Sommige van hierdie soort studies is egter beperk omdat hulle nie
gekompenseer het vir kovariante van hipertrofie nie.
Om hierdie hipotese te ondersoek, is die genotipe bepaal by een-en-twintig polimorfiese lokusse,
verspreid regoor ses RAAS gene (ACE1, AGT, AGTR1, CYP11B2, CMA and ACE2), in 353
kandidate vanuit 22 Suid-Afrikaanse HCM-families in wie stigter mutasies segregeer. Genotipes was
vergelyk met 17 eggokardiografies afgeleide hipertrofiese indekse van linker ventrikulêre wanddikte
by 16 segmente wat oor drie longitudinale vlakke strek. Familie-gebaseerde assosiasies was
bestudeer deur kwantitatiewe transmissie disequilibrium toetsing (QTDT) en gemengde effek
modelle om die X-gekoppelde geen ACE2 te analiseer, met gelyktydige kompensasie vir hipertrofie
kovariate (ouderdom, geslag, sistoliese bloed druk (BP), diastoliese BP, liggaamsoppervlak area,
hartritme en mutasie-status).
Sterk indikasies van koppeling in die afwesigheid van assosiasie is waargeneem tussen ACE1
lokusse en posterior wanddikte (PW) asook anterior wanddikte (AW) by die papillêre spier vlak
(pap) en die apeks vlak (apx). In enkel-lokus analises is statisties-betekenisvolle assosiasies gevind
tussen die CYP11B2 rs3097 polimorfisme en PW by die mitraalklep vlak (mit) en beide die PWpap
en inferior wanddikte (IW)pap. Statisties-betekenisvolle assosiasies was verder gevind by drie
AGTR1 polimorfismes, naamlik, tussen rs2640539 polimorfisme en AWmit, rs3772627 en die
anterior interventrikulêre septumdikte (aIVS) by die pap en rs5182 by beide die IWpap en AWapx.
Gemengde-effek modelle het verder assosiasies aangetoon tussen die ACE2 rs879922 polimorfisme
en die posterior interventrikulêre septumdikte en die laterale wanddikte by die mit, slegs in vrouens.
Hierdie data dui op ‘n kovariaat-onafhanklike rol vir RAAS genetiese variante in die modifisering
van die fenotipiese uitdrukking van hipertrofie in HCM-geaffekteerde individue.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/21880 |
| Date | 03 1900 |
| Creators | Cloete, Ruben Earl Ashley |
| Contributors | Corfield, Valerie A., Moolman-Smook, Johanna C., Van der Merwe, Lize, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | xx, 234 leaves : ill. |
| Rights | Stellenbosch University |
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