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. 2023 Jun;38(6):1793-1800.
doi: 10.1007/s00467-022-05789-7. Epub 2022 Nov 10.

Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome

Mallory L Downie  1   2 , Sanjana Gupta  1 , Melanie M Y Chan  1 , Omid Sadeghi-Alavijeh  1 , Jingjing Cao  3 , Rulan S Parekh  3   4 , Carmen Bugarin Diz  5 , Agnieszka Bierzynska  6 , Adam P Levine  7 , Ruth J Pepper  1 , Horia Stanescu  1 , Moin A Saleem  6 , Robert Kleta  1   2 , Detlef Bockenhauer  1   2 , Ania B Koziell  5 , Daniel P Gale  8
Affiliations

Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome

Mallory L Downie et al. Pediatr Nephrol. 2023 Jun.

Abstract

Background: Idiop athic 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 in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways.

Methods: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls.

Results: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS.

Conclusions: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Focal segmental glomerulosclerosis; Genetic risk score; Minimal change disease; Monogenic; Paediatrics; Steroid-resistant nephrotic syndrome; Steroid-sensitive nephrotic syndrome.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
A higher resolution version of the Graphical abstract is available as Supplementary information
Fig. 1
Fig. 1
Genetic Risk Scores in SSNS, SRNS, MCD, and FSGS are elevated compared with control cohorts and monogenic INS. A Distribution of genetic risk scores in non-monogenic and monogenic INS compared to healthy controls. The x-axis represents SSNS-GRS. Median values for each group are represented by vertical lines with distribution of SSNS-GRS displayed through density plots for each cohort. Asterisks indicate p <0.007 using the Kruskal–Wallis test with correction for planned comparisons to healthy controls. B Density of SSNS-GRS in individuals with monogenic versus autoimmune INS. C ROC curve for monogenic versus autoimmune INS. SSNS, steroid-sensitive nephrotic syndrome; MCD, minimal change disease; SRNS, steroid-resistant nephrotic syndrome; FSGS, focal segmental glomerulosclerosis; INS, idiopathic nephrotic syndrome; GRS, genetic risk score; ROC, receiver operating characteristic
See this image and copyright information in PMC

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