Harrison, S; (2013) Using genomic data to understand novel pathways in Abdominal Aortic Aneurysm. Doctoral thesis (PhD), UCL (University College London).

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Abstract

In this thesis, following development of extensive research collaborations, I use genetic epidemiology methods to understand disease pathways in abdominal aortic aneurysm (AAA). In the first replication study of a variant in DAB2IP found to be associated with AAA by genome wide association study I found that rs7025486 was consistently associated with higher risk of both AAA and coronary heart disease in newly genotyped studies, but was not associated with a panel of emerging cardiovascular biomarkers and did not interact with the 9p21 cardiovascular disease locus. Using a Mendelian Randomisation (MR) approach I provide strong statistical evidence that signaling through the interleukin-6 receptor is likely to be a causal pathway in AAA and may therefore represent a valid therapeutic target. Extending the MR paradigm, by utilizing multiple genetic variants combined into a score I provide evidence that HDL-C mediated pathways may also be causal in AAA, in support of a meta-analysis I performed that shows strong association between HDL-C concentration and AAA. Finally, by using a novel quantitative trait genomics approach I performed a gene centric scan of carotid artery remodelling and found variants on Chromosome 1 in DNM3-PIGC to be associated with both carotid artery size and risk of AAA, providing compelling evidence that AAA is a focal manifestation of a systemic dilating disease.

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