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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Genome-Wide Association Study
  • Glomerulonephritis, Membranous*
  • Glomerulosclerosis, Focal Segmental* / diagnosis
  • Glomerulosclerosis, Focal Segmental* / drug therapy
  • Glomerulosclerosis, Focal Segmental* / genetics
  • Humans
  • Nephrosis, Lipoid* / diagnosis
  • Nephrosis, Lipoid* / drug therapy
  • Nephrosis, Lipoid* / genetics
  • Nephrotic Syndrome* / diagnosis
  • Nephrotic Syndrome* / drug therapy
  • Nephrotic Syndrome* / genetics
  • Risk Factors
  • Steroids


  • Steroids

Supplementary concepts

  • Nephrosis, congenital