Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular morbidity and allcause
mortality. Significantly, it is considered a modifiable cardiovascular risk factor as its
regression increases overall survival and reduces the frequency of adverse cardiac events. A clear
understanding of LVH pathogenesis is thus imperative to facilitate improved risk stratification and
therapeutic intervention.
Hypertrophic cardiomyopathy (HCM), an inherited cardiac disorder, is a model disease for
elucidating the molecular mechanisms underlying LVH development. LVH, in the absence of
increased external loading conditions, is its quintessential clinical feature, resulting from mutations
in genes encoding sarcomeric proteins. The LVH phenotype in HCM exhibits marked variability
even amongst family members who carry the same disease-causing mutation. Phenotypic
expression is thus determined by the causal mutation and additional determinants including the
environment, epigenetics and modifier genes.
Thus far, factors investigated as potential hypertrophy modifiers in HCM have been relatively
removed from the primary stimulus for LVH; and the few studies that have been replicated yielded
inconsistent results. We hypothesized that the factors that closely interact with the primary stimulus
of faulty sarcomeric functioning, have a greater capacity to modulate it, and ultimately the LVH
phenotype in HCM. Plausible candidate modifiers would include factors relating to the structure or
function of the sarcomere, including known HCM-causal genes; and the enzymes that function in
sarcomere-based energetics. Indeed, the literature highlights the relevance of sarcomeric proteins,
Ca2+-handling and myocardial energetics in the development of LVH in HCM.
This study, therefore, set out to evaluate the hypertrophy-modifying capacity of such factors by
means of family-based genetic association testing in 27 South African HCM families in which one
of three unique HCM-causing founder mutations segregates. Moreover, the single and combined
effects of 76 variants within 26 candidate genes encoding sarcomeric or sarcomere-associated
proteins were investigated.
The study identified a modifying role in the development of hypertrophy in HCM for each of the
candidate genes investigated with the exception of the metabolic protein-encoding gene, PRKAG1.
More specifically, single variant association analyses identified a modifying role for variants within the genes MYH7, TPM1 and MYL2, which encode proteins of the sarcomere, as well as the genes
CPT1B, CKM, ALDOA and PRKAB2, which encode metabolic proteins. Haplotype-based
association analyses identified combined modifying effects for variants within the genes ACTC,
TPM1, MYL2, MYL3 and MYBPC3, which encode proteins of the sarcomere, as well as the genes
CD36, PDK4, CKM, PFKM, PPARA, PPARG, PGC1A, PRKAA2, PRKAG2 and PRKAG3, which
encode metabolic proteins. Moreover, a number of variants and haplotypes showed statistically
significant differences in effect amongst the three HCM founder mutation groups.
The HCM-modifier genes identified were prioritised for future studies according to the number of
significant results obtained for the four tests of association performed. The genes TPM1 and
MYBPC3, which encode sarcomeric proteins, as well as the genes PFKM and PRKAG2, which
encode metabolic proteins, were identified as stronger candidates for future studies as they
delivered multiple significant results for various statistical tests.
This study makes a novel contribution to the field of hypertrophy research as it tested the
hypothesis that structural or energy-related factors located within the sarcomere may act as
modifiers of cardiac hypertrophy in HCM, and succeeded in identifying a modifying role for many
of the candidate genes selected. The significant results include substantial single and within-genecontext
variant effects; and identified sizeable variation in the risk of developing LVH owing to the
compound effect of the modifier and the individual founder mutations. Collectively, these findings
enhance the current understanding of genotype/phenotype correlations and may, as consequence,
improve patient risk stratification and choice of treatment. Moreover, these findings emphasize the
potential for modulation of disease by further elucidation of some of the avenues identified. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is ‘n onafhanklike voorspeller van kardiovaskulêre
morbiditeit en van mortaliteit weens alle oorsake. Van belang is dat dit ‘n wysigbare
kardiovaskulêre risiko faktor is, aangesien die afname daarvan algehele oorlewing verhoog en die
frekwensie van nadelige kardiale voorvalle verlaag. ‘n Duidelike begrip van LVH patogenese is dus
noodsaaklik om verbeterde risiko stratifikasie en terapeutiese intervensie te fasiliteer.
Hipertrofiese kardiomiopatie (HKM), ‘n oorerflike hart-siekte, is ‘n model-siekte vir die uitpluis
van die molekulêre meganismes onderliggend aan die ontwikkeling van LVH. LVH, in die
afwesigheid van verhoogde eksterne lading, is die kern kliniese simptoom van HKM en die gevolg
van mutasies in die gene wat kodeer vir sarkomeriese proteïene. Die LVH fenotiepe in HKM toon
merkbare veranderlikheid selfs in familie-lede wat dieselfde siekte-veroorsakende mutasie dra. Die
fenotiepe word dus bepaal deur die siekte-veroorsakende mutasie asook addisionele determinante
insluitend die omgewing, epigenetika en modifiserende gene.
Potensiële hipertrofie-modifiseerders wat tot dusver bestudeer is, is betreklik verwyder van die
primêre stimulus vir LVH en die paar studies wat gerepliseer is, het teenstrydige resultate gelewer.
Ons hipoteseer dat die faktore wat in noue interaksie met die primêre stimulus van foutiewe
sarkomeriese funksionering is, ‘n groter kapasitieit het om dit en uiteindelik die LVH fenotiepe in
HKM, te moduleer. Aanneemlike kandidaat-modifiseerders sou insluit faktore wat betrekking het
tot die struktuur en funksie van die sarkomeer insluitend HKM-oorsaaklike gene en die ensieme wat
funksioneer in sarkomeer-gebaseerde energetika. Die literatuur beklemtoon inderdaad die relevansie
van sarkomeriese proteïene, Ca2+-hantering en miokardiese energetika in die ontwikkeling van
LVM in HKM.
Hierdie studie het beoog om die hipertrofie-modifiserende kapasiteit van sulke faktore te evalueer
deur middel van familie-gebaseerde genetiese assosiasie toetse in 27 Suid-Afrikaanse HKM
families waarin een van drie unieke HKM-stigter mutasies segregeer. Verder was die enkel en
gekombineerde effekte van 76 variante binne 26 kandidaat gene wat kodeer vir sarkomeer en
sarkomeer-geassosieerde proteïene, ondersoek.
Hierdie studie het ‘n modifiserende rol in die ontwikkeling van hipertrofie in HKM geïdentifiseer
vir elk van die kandidaat gene wat ondersoek is, met uitsluiting van die PRKAG1, wat kodeer vir ‘n
metaboliese proteïen. Meer spesifiek, enkel variant assosiasie analises het ‘n modifiserende rol
geïdentifiseer vir variante in die gene MYH7, TPM1 en MYL2, wat kodeer vir sarkomeriese
proteïene, asook die gene CPT1B, CKM, ALDOA en PRKAB2, wat kodeer vir metabolise proteïene.
Haplotipe-gebaseerde assosiasie-analises het gekombineerde modifiserende effekte geïdentifiseer
vir variante in die gene ACTC, TPM1, MYL2, MYL3 en MYBPC3, wat kodeer vir strukturele
proteïene van die sarkomeer asook die gene CD36, PDK4, CKM, PFKM, PPARA, PPARG, PGC1A,
PRKAA2, PRKAG2 en PRKAG3, wat kodeer vir metabolise proteïene. Verder het ‘n aantal variante
en haplotipes statisties betekenisvolle verskille in effek tussen die drie HKM-stigter mutasie groepe
getoon.
Die HKM-modifiserende gene wat geïdentifiseer is, is verder geprioritiseer vir toekomstige studies
volgens die aantal beduidende resultate wat vir die vier assosiasie toetse verkry is. Die gene TPM1
and MYBPC3, wat kodeer vir sarkomeriese proteïene, asook die gene PFKM and PRKAG2, wat
kodeer vir metaboliese proteïene, is geïdentifiseer as sterker kandidate vir verdere studies omdat
veelvuldige beduidende resultate vir die verskeie statistiese toetse deur hulle gelewer is.
Hierdie studie maak ‘n nuwe bydrae tot die veld van hipertrofie navorsing omdat dit die hipotese
dat strukturele en energie-verwante faktore, wat binne die sarkomeer geposisioneer is, potensieel as
modifiseerders van kardiale hipertropfie in HKM kan optree, ondersoek het. Dit slaag ook daarin
om ‘n modifiserende rol vir baie van die geselekteerde kandidaatgene te identifiseer. Die
beduidende resultate sluit in aansienlike enkel en binne-geen-konteks variant-effekte en aansienlike
variasie in die risiko vir LVH ontwikkeling verskuldig aan die gekombineerde effek van
modifiseerder en individuele stigter mutasies. Gesamentlik verbeter hierdie bevindinge die huidige
begrip van genotipe/fenotipe korrelasies en dit mag tot gevolg hê verbeterde pasiënt risiko
stratifikasie en keuse van behandeling. Verder beklemtoon hierdie bevindinge die potensiaal vir
siekte modulering deur verdere uitpluis van sekere van hierdie geïdentifiseerde navorsingsrigtings. / National Research Foundation / Dr. Paul van Helden / Stellenbosch University
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/79795 |
| Date | 03 1900 |
| Creators | Bloem, Liezl Margaretha |
| Contributors | Moolman-Smook, J. C., Van der Merwe, L., 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 | Unknown |
| Type | Thesis |
| Format | xxx, 253 p. : ill., some col. |
| Rights | Stellenbosch University |
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