The effect of immunogenetic variability on human health: bioinformatics investigations from different perspectives



Takeshita, LYC
(2018) The effect of immunogenetic variability on human health: bioinformatics investigations from different perspectives. PhD thesis, University of Liverpool.

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Abstract

The high level of diversity exhibited by genes coding for molecules involved in the immune system are critically involved with several aspects of human health. The ability of the immune system to recognize foreign pathogens or abnormal cells, while tolerating itself is achieved through a balance of various components and receptors in the immune system. Individual genotypes of immune genes such as HLA and KIR fine-tune this balance. Variability in those genes lead to diversity in the response to foreign molecules, and can also lead to intolerance to self-molecules in the form of autoimmune responses. Several past studies have found HLA and KIR polymorphisms to be associated with susceptibility or protection to a range of diseases and hypersensitivity to drugs. HLA has also a major role in transplantation, where transplanted tissues need to be as similar as possible to avoid rejection. The work described in this thesis contributes towards the knowledge of immunogenetic implications in associations with diseases, transplantation and adverse reactions to drugs using different bioinformatics approaches. First, it provides bioinformatics resources for a better understanding of the impact of immunogenetic diversity on human health in the form of two public databases, alongside with insights obtained through the analysis of their contents. The KIR and Disease Database (KDDB), described in Chapter 2, stores disease associations with KIR genes expressed in natural killer cells. The data within KDDB has been analysed to uncover trends within studies, in terms of the sets of KIR genes associated with susceptibility to, or protection from, auto-immune diseases, infectious diseases, pregnancy complications and cancer. The HLA Epitope Frequency Database (EpFreq-DB), described in Chapter 3, stores population frequencies of HLA epitopes, which are structural units on the surface of HLA molecules that have been increasingly associated with improvements in transplantation matching. An analysis has been performed to demonstrate global differences in the carriage of particular epitopes, and the potential functional consequences of using epitope mapping, instead of the more traditional allele matching for transplantation scenarios. Lastly, it investigates the molecular mechanisms underlying the association HLA polymorphisms with severe hypersensitivity caused by the anti- retroviral drug nevirapine, using molecular docking approaches. Developments described in this thesis contribute to better understanding of the influence of immune variability in human health and provides necessary knowledge to advances in personalized medicine.

Item Type: Thesis (PhD)
Divisions: Fac of Health & Life Sciences > Faculty of Health and Life Sciences
Depositing User: Symplectic Admin
Date Deposited: 16 Aug 2018 14:27
Last Modified: 03 Mar 2021 10:31
DOI: 10.17638/03020019
Supervisors:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3020019