Genetic determinants of cardiac traits
Author(s)
Ahmed, Rizwan
Type
Thesis
Abstract
Background: The heritability and genomic determinants of cardiac traits such as
coronary flow (CF), coronary flow reserve (CFR), myocardial relaxation (LV dP/dtmin)
and myocardial contractility (LV dP/dtmax) remain unknown. Brown Norway (BN) and
Spontaneously Hypertensive Rat (SHR) are genetically distant inbred rat strains with
distinct cardiovascular phenotypes. Genome sequence for both the strains is available
making it possible to identify genetic determinants of cardiac phenotypes.
Aims: To establish the heritability of cardiac traits, identify novel quantitative trait
loci (QTLs) underlying these traits and to prioritize candidate genes by integrating information
from physiological trait analysis with genome sequence and transcriptional
profiling of cardiac tissue in an intercross derived from BN and SHR.
Methods: Cardiac phenotyping was carried out in the parental BN and SHR strains
as well as an intercross derived from these strains using in vivo blood pressure (BP) profiling
and ex vivo Langendorff preparation. Genome-wide SNP genotyping was performed
using a custom genotyping assay and transcriptional profiling of non-ischaemic cardiac
tissue was undertaken on a subset of the intercross (n =110).
Results: All cardiac traits studied were at least as heritable as BP. Novel QTLs were
discovered for CF, CFR, LV dP/dtmin and LV dP/dtmax as well as confirming previously
documented QTLs for BP and cardiac mass. A significant proportion of trait heritability
was explained by genetic variation utilizing multiple QTL models. Expression analysis
revealed cis and trans genomic control regions for cardiac gene expression. Expression
QTL (eQTL) hot spots on rat chromosomes 3 and 8 were shown to be significantly enriched
for regulation of mitochondrial transcripts and these regions were also linked to cardiac
mass suggesting correlation between mitochondrial function and cardiac mass.
coronary flow (CF), coronary flow reserve (CFR), myocardial relaxation (LV dP/dtmin)
and myocardial contractility (LV dP/dtmax) remain unknown. Brown Norway (BN) and
Spontaneously Hypertensive Rat (SHR) are genetically distant inbred rat strains with
distinct cardiovascular phenotypes. Genome sequence for both the strains is available
making it possible to identify genetic determinants of cardiac phenotypes.
Aims: To establish the heritability of cardiac traits, identify novel quantitative trait
loci (QTLs) underlying these traits and to prioritize candidate genes by integrating information
from physiological trait analysis with genome sequence and transcriptional
profiling of cardiac tissue in an intercross derived from BN and SHR.
Methods: Cardiac phenotyping was carried out in the parental BN and SHR strains
as well as an intercross derived from these strains using in vivo blood pressure (BP) profiling
and ex vivo Langendorff preparation. Genome-wide SNP genotyping was performed
using a custom genotyping assay and transcriptional profiling of non-ischaemic cardiac
tissue was undertaken on a subset of the intercross (n =110).
Results: All cardiac traits studied were at least as heritable as BP. Novel QTLs were
discovered for CF, CFR, LV dP/dtmin and LV dP/dtmax as well as confirming previously
documented QTLs for BP and cardiac mass. A significant proportion of trait heritability
was explained by genetic variation utilizing multiple QTL models. Expression analysis
revealed cis and trans genomic control regions for cardiac gene expression. Expression
QTL (eQTL) hot spots on rat chromosomes 3 and 8 were shown to be significantly enriched
for regulation of mitochondrial transcripts and these regions were also linked to cardiac
mass suggesting correlation between mitochondrial function and cardiac mass.
Date Issued
2012-07
Date Awarded
2012-09
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Cook, Stuart
Sponsor
British Heart Foundation
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)