1. Shared genetic risk across different presentations of gene test–negative idiopathic nephrotic syndrome.
- Author
-
Downie, Mallory L., Gupta, Sanjana, Chan, Melanie M. Y., Sadeghi-Alavijeh, Omid, Cao, Jingjing, Parekh, Rulan S., Diz, Carmen Bugarin, Bierzynska, Agnieszka, Levine, Adam P., Pepper, Ruth J., Stanescu, Horia, Saleem, Moin A., Kleta, Robert, Bockenhauer, Detlef, Koziell, Ania B., and Gale, Daniel P.
- Subjects
NONPARAMETRIC statistics ,KRUSKAL-Wallis Test ,SEQUENCE analysis ,NEPHROTIC syndrome ,STEROIDS ,GENETIC testing ,GENETIC variation ,GENETIC polymorphisms ,RISK assessment ,GENOME-wide association studies ,DESCRIPTIVE statistics ,RESEARCH funding ,DATA analysis software ,DISEASE risk factors ,CHILDREN - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF