WIP 49 - JAK/STAT Pathway Genetic Variants and Expression in MCD and FSGS: A CureGN and NEPTUNE Study

Publication Number: WIP 49.7551

Meghana Karan, Cohen Children's Medical Center, Kew Gardens, NY, United States; Matthew Schuchman, Cohen Children's Medical Center, New Hyde Park, NY, United States; Sean Eddy, University of Michigan Medical School, Ann Arbor, MI, United States; Katie Margolis, Cohen Children's Medical Center, New Hyde Park, NY, United States; Danielle Diem, Cohen Children's Medical Center, New Hyde Park, NY, United States; Mahie M. Abdullah, Cohen Children's Medical Center, Bronx, NY, United States; Suzanne Vento, Cohen Children's Medical Center, New Hyde Park, NY, United States; Laura Castellanos Reyes, Cohen Children's Medical Center, New Hyde Park, NY, United States; Pamela Singer, Cohen Children's Medical Center, New Hyde Park, NY, United States; Abby Basalely, Cohen childrens medical center, New Hyde park, NY, United States; Christine Sethna, Cohen Children's Medical Center, New Hyde Park, NY, United States; Jennifer Yee, University of Michigan Medical School, Ann Arbor, MI, United States; Carol L. Shen, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, United States

Background: Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are the most common diagnoses in nephrotic syndrome (NS), which results from a defective glomerular filtration barrier, causing massive proteinuria and edema. Genetic forms of NS are a major cause of nonresponse to treatment, leading to end stage kidney disease. The known genetic architecture of NS ranges from highly penetrant, pathogenic variants in single genes to common risk alleles. Previously, the JAK/STAT inflammatory pathway has been implicated in various kidney diseases. In addition, we have recently identified a JAK1 gain-of-function mutation in a pediatric patient with membranous nephropathy. Our previous work also showed that STAT3 activity in T-cells correlates with FSGS severity and predicts worse outcomes.

Objective: Taking advantage of a large cohort of patients with NS followed longitudinally in the Nephrotic Syndrome Study Network (NEPTUNE) and Cure Glomerulonephropathy (CureGN) with whole genome sequencing data, this study aims to (1) identify putative pathogenic variants in the JAK/STAT pathway, (2) calculate JAK/STAT transcriptional activity scores, and (3) determine the correlation of the above with clinical outcomes of adults and children with FSGS and MCD. We hypothesize that pathogenic JAK/STAT variants or pathway activity scores are associated with disease severity and progression of NS.

Design/Methods: A customized bioinformatics pipeline will be applied to identify putative pathogenic variants in the JAK/STAT pathway in patients with available whole genome sequencing data (n=425 from NEPTUNE, n=908 from CureGN). JAK/STAT transcriptional activity scores will be calculated from the available tissue and whole blood transcriptomic signatures. The discovered pathogenic variants and the pathway activity scores will be correlated to clinical outcomes including remission status and kidney function decline using multivariable regression and survival analyses.
This study is an approved NEPTUNE/CureGN ancillary study and has IRB approval. This study will be completed by April 2025.