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Title: Genotype-phenotype relations in lupus nephritis
Author: Jordan, Natasha Patricia
ISNI:       0000 0004 5368 0492
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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This thesis explores genotype-phenotype relations in lupus nephritis. Over the past decade, advances in genetic research have improved our understanding of the genes that contribute to lupus susceptibility. However a clear understanding of how these genetic factors interact with the immune system to produce disease in a given patient or group of patients with SLE is difficult to define at this time. Recent monogenic causes of SLE have provided valuable insights into lupus pathogenesis. A comprehensive clinical characterisation of 164 biopsy proven lupus nephritis patients was undertaken in the initial phase of this research. 27% of patients recruited were of juvenile onset, as defined by diagnosis of nephritis before 18 years of age. Non-European lupus nephritis patients had a younger age of onset and higher rate of progression to end-stage renal disease. Sixteen individuals had a first degree family history of lupus nephritis including five sibling pairs. Familial clustering of nephritis was associated with juvenile onset disease and a more severe clinical phenotype. The entire cohort was genotyped by ImmunoChip for known lupus susceptibility polymorphisms. Associations with lupus nephritis were found in polymorphisms in the HLA region, IRF5, ITGAM, STAT4, TNFAIP3, TNFSF4 and ETS1. Whole Exome Sequencing of familial lupus nephritis cases identified a large number of potential candidates for functional investigation. A promising short list of candidates was created using pedigree information, focusing on variants predicted to be damaging and by incorporating prior knowledge of the biologic pathways implicated in lupus. Candidates under consideration for functional testing include genes involved in activation of Ras pathways, genes involved in the antioxidant defence system, variants in ubiquitination pathways, mutations in serine/threonine protein kinases and genes involved in toll-like receptor and type I interferon signalling pathways.
Supervisor: Geissmann, Frederic Henri Lucien Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available