Alg, Varinder Singh;
(2022)
Genetic and Observational Subarachnoid Haemorrhage (GOSH) Study - A UK-wide clinical and genetic cohort study of aneurysmal subarachnoid haemorrhage.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Introduction: Intracranial aneurysms affect 2-5% of the general population.1 A tiny proportion of these rupture leading to aneurysmal subarachnoid haemorrhage (SAH), which can be fatal instantly or lead to life-changing neurological morbidity in a young group of stroke survivors. Understanding the pathophysiological mechanisms underlying intracranial aneurysms, and being able to predict which patients have a higher risk of rupture has led to intensive research efforts, via epidemiological, molecular and genetic studies. Our aim was to determine the association of candidate genes with intracranial aneurysms in a large UK Caucasian population. Methods: We performed a case-control genetic association study of single nucleotide polymorphisms (SNPs) in over 1600 patients with intracranial aneurysms from a UK-wide Genetic and Observational Subarachnoid Haemorrhage (GOSH) study and 1500 controls from the Wellcome cohort,2 utilising a candidate-gene approach. We conducted a literature review and performed a meta-analysis of the existing candidate gene studies to better determine which genes would be suitable for analysis in our cohort. We also performed a new meta-analysis using our data for each SNP examined to determine if our genetic associations with intracranial aneurysms were robust. Results: We examined 22 SNPs related to vascular endothelial integrity, the extracellular matrix, and inflammation. Two SNPs showed associations with intracranial aneurysms in our UK cohort: the D allele of ACE Insertion/Deletion SNP (associated with vascular endothelial function; OR 1.14 [1.02-1.28], p=0.02) and the MMP-2 C>T rs243865 SNP (associated with extracellular matrix integrity; OR 1.18 [1.04 – 1.33], p=0.012). Conclusions: We found associations with intracranial aneurysms for the D allele of the ACE I/D SNP, and a potentially functionally significant MMP-2 SNP. Both genes have plausible connections to IA pathophysiology (endothelial function and extracellular matrix integrity, respectively), and could potentially predispose patient to aneurysm rupture as demonstrated by sub-group analysis.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Genetic and Observational Subarachnoid Haemorrhage (GOSH) Study - A UK-wide clinical and genetic cohort study of aneurysmal subarachnoid haemorrhage |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10143186 |
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