Downie, Mallory Lorraine;
(2022)
Using genetics to understand childhood nephrotic syndromes.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Idiopathic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS), and for rarer causes, according to kidney histology, which includes idiopathic membranous nephropathy (MN) among others. The genetics of these INS subtypes have been partially elucidated, but several important questions remain. This thesis has three aims: 1) to investigate the potential for a risk locus on the X chromosome in MN; 2) to identify the genetic variants associated with SSNS in patients of Sri Lankan ancestry; and 3) to determine whether a genetic risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of SRNS. First, we identified linkage of familial MN to chromosome Xp11.3-11.22 (2Mb, LOD 3.260) in 3 families with 8 affected males. Affected individuals were negative for anti-PLA2R antibodies and had a significantly lower genetic risk score (GRS) than individuals with the more common, anti- PLA2R-associated MN, suggesting that X-linked familial MN represents a separate aetiologic entity. Second, we identified two genome-wide significant loci (HLA-DQA1, rs9271602, OR=2.75, p=5.34x10-28; TMEM131L, rs74537360, OR=2.36, p=3.47x10-8) in Sri Lankan patients with SSNS (n=420) compared to controls (n=2339), supporting the hypothesis for an underlying immunologic basis in SSNS. We also performed a trans-ethnic meta-analysis with a European cohort and identified a novel association in AHI1 (rs2746432, OR 1.36, p=2.80x10-8) with SSNS. Lastly, we developed an SSNS-GRS and found that compared with controls and those with monogenic disease, SSNS-GRS was significantly elevated in patients with both SSNS and SRNS. Accordingly, we propose that INS would be better classified as either monogenic or immune-mediated podocytopathy rather than by response to empirical corticosteroid therapy. This thesis highlights the discovery of a novel locus on the X-chromosome linked to familial MN, novel loci in TMEM131L and AHI1 associated with Sri Lankan SSNS, and a proposed reclassification of INS nomenclature based on shared genetic risk between subtypes of non-monogenic INS.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Using genetics to understand childhood nephrotic syndromes |
| 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. |
| Keywords: | nephrotic syndrome, genetics, genome-wide association study, genetic risk score, linkage analysis |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10155810 |
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