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Genetic determinants of cardiac traits

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Title: Genetic determinants of cardiac traits
Authors: Ahmed, Rizwan
Item Type: Thesis or dissertation
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.
Issue Date: Jul-2012
Date Awarded: Sep-2012
URI: http://hdl.handle.net/10044/1/10138
DOI: https://doi.org/10.25560/10138
Supervisor: Cook, Stuart
Sponsor/Funder: British Heart Foundation
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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