Clinical, genetic and molecular aspects of membranous nephropathy.
Doctoral thesis, UCL (University College London).
Membranous Nephropathy (MN) is one of the leading causes of end-stage renal disease (ESRD). MN is an autoimmune disease in which autoantibodies target antigens at the level of the glomerular basement membrane. The nature of these antibodies and the reason why they develop are not fully understood. One of the strategies towards a better understanding of the disorder is genetic analysis, of which two approaches have been attempted: linkage mapping, based on a family suggestive for X-linked transmission of the MN trait; and whole genome association mapping, based on three case-control cohorts. The first cohort (335 cases and ethnically matched controls from the UK) was genotyped using SNP markers and analysed in an exploratory study which led to the identification of two highly significant loci of association. Two cohorts (146 biopsy proven MN cases and ethnically matched controls from the Dutch research group in Nijmegen and 75 biopsy proven cases and ethnically matched controls from the French research group in Paris) were used to successfully replicate the results. The two loci which we identified and independently confirmed are located on chromosome 2 and on chromosome 6. The chromosome 2 locus includes the PLA2R gene, confirming the hypothesis of Beck et al. which identified PLA2R as a key antigen in idiopathic MN by using an immunological approach . The chromosome 6 locus lies within the extended Human Leukocyte Antigene (HLA) system locus, with the highest significance for association reached by alleles of HLA-DQA1. Our results suggest that the susceptibility to membranous nephropathy is associated to genetic variants at the level of both PLA2R1 and HLA loci. The causative variants could be some of the polymorphisms captured by the genotyping array which was analysed or, more likely variants (single nucleotide or copy number variant type) situated nearby (and therefore in linkage disequilibrium).
|Title:||Clinical, genetic and molecular aspects of membranous nephropathy|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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