Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/2937
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dc.contributor.authorMartin, Ruairidh Iain Russell.-
dc.date.accessioned2016-05-06T14:27:04Z-
dc.date.available2016-05-06T14:27:04Z-
dc.date.issued2015-
dc.identifier.urihttp://hdl.handle.net/10443/2937-
dc.descriptionPhD Thesisen_US
dc.description.abstractGenome wide association studies (GWAS) have identified multiple loci which are associated with increased risk of atrial fibrillation (AF). The mechanisms underlying these associations are not understood. None of the variants identified result in alteration of coding sequences; they are therefore likely to act by altering gene expression. Identification of intermediate gene expression phenotypes which are associated with the risk variants could provide important insights into disease pathogenesis which could in turn lead to development of therapeutic targets. One of the genetic variants identified by GWAS is situated within an intron of the gene HCN4, which encodes the major component of the If pacemaker current. This raised the question whether lower activity of HCN4 could be a risk factor for AF. By performing meta-analysis of randomised controlled trials of ivabradine, an If inhibitor, I demonstrated an increase in relative risk of incident AF of 15% in patients treated with ivabradine vs. controls, supporting the role of HCN4 in AF susceptibility. Analysis of total expression and allelic expression ratios of candidate genes in the GWAS hit regions in whole blood identified associations between AF risk variants and increased expression of KCNN3 and SYNE2 and decreased expression of CAV1. Analysis of total expression and allelic expression ratio in right atrial appendage tissue identified further associations between AF risk variants and increased expression of PITX2a/b and decreased expression of MYOZ1, CAV1, C9orf3 and FANCC in right atrial tissue. Furthermore, although the experiments were not designed to detect difference between AF cases and controls, I have shown that AF is associated with reduced expression of SYNE2, HCN4 and CAV1.en_US
dc.description.sponsorshipBritish Heart Foundationen_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleInvestigation of the mechanisms mediating genetic associations with atrial fibrillationen_US
dc.typeThesisen_US
Appears in Collections:Institute of Genetic Medicine

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