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Title: Genome wide association study in steroid sensitive nephrotic syndrome
Author: Dufek-Kamperis, Stephanie
ISNI:       0000 0004 9353 0499
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available