Abdominal aortic aneurysm (AAA), age-related macular degeneration (AMO) and invasive meningococcal disease (IMO) are multifactorial diseases which have genetic and environmental risk factors. The complement system is an ancient part of the innate immune system that is activated in all three of these diseases. AAA is a pathological dilatation of the abdominal aorta that can rupture, often causing death. AMD is a common sight-impairing inflammatory retinal disease. IMD is due to infection with Neisseria meningilidis, which can cause potentially fatal illness in some people. The aim of this work is to better understand the effect of human genetic polymorph isms on susceptibility to these diseases. Genome-wide association study data from collaborators (for AAA) and a public data repository (for AM D) were reanalysed to find novel genetic risk factors. Replication studies were conducted for both of these investigations. Complement system candidate gene studies were conducted for AAA, AMD and IMD using primer extension and sequencing methods. Genetic risk factors for AAA were identified in the genome-wide study, one of which, rs6511720 T in low density lipoprotein receptor (LDLR) , was associated at genome-wide significance (odds ratio 0.78; 95% confidence interval 0.69-0.86; P= 1.03x10-s). Complement gene polymorphisms were not found to be important for AAA risk. A coding polymorphism in CFB, rs12614, was identified as a novel independent risk factor for AMD. The AMD genome-wide study reanalysis identified several bio logically plausible loci that did not reach significance in a small follow-up study. Investigation of complement genes in IMO revealed that MBL2 structural polymorphisms, previously reported to be of major importance, were not associated. The AMO- and IMO-associated CFH locus was characterised in detail. The results of these investigations improve understanding of the pathogenesis of all three diseases. This knowledge may play a part in facilitating the development of new preventative and therapeutic strategies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600124 |
| Date | January 2013 |
| Creators | Bradley, Declan Terrance |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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