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Genome wide association study in steroid sensitive nephrotic syndrome

Dufek-Kamperis, Stephanie; (2020) Genome wide association study in steroid sensitive nephrotic syndrome. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Steroid sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood is considered a complex disease with the immune system playing a critical role in its development. This is supported by recent molecular findings showing an association with classical human leukocyte antigen; yet, the exact nature of the disease, specifically the genetic architecture outside the HLA region, has not been elucidated. With this thesis we aimed to explore the genetics of SSNS by performing a genome-wide association study on a cohort of 422 European cases and 5642 ethnically matched controls with more than 5 million high-quality imputed genome-wide markers. Our results revealed three loci achieving genome-wide significance in association with the disease. The strongest association was found within the HLA-DR/DQ region (lead variant rs9273542, p=1.59×10-43, OR=3.39, 95%CI=2.86-4.03) confirming findings of previous GWAS. Moreover, we are the first reporting on two loci outside the HLA region on chromosome 6q22.1 and 4q13.3 that are associated with SSNS with genome-wide significance. The region on chromosome 6q contains the gene CALHM6, which has been implicated in the regulation of the immune system and is particularly expressed on CD4+ cells and naïve and memory B cells. The identified lead variant (rs2637678, p=1.27×10-17, OR=0.51, 95%CI=0.44-0.60) is a strong expression quantitative trait locus (eQTL) for CALHM6, with the risk allele predicting lower expression of CALHM6 on lymphocytes and hence possibly altered immune regulatory responses. The same variant is also an eQTL for the neighbouring gene DSE, which codes for an enzyme essential in the dermatan sulfate production. Overexpression of dermatan sulfate has been previously associated with glomerular diseases and could be a potential antigen involved in SSNS. These findings support the hypothesis that the immune system and its dysregulation play a critical role in the pathogenesis of SSNS.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genome wide association study in steroid sensitive nephrotic syndrome
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
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 > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10095103
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