# Defining the Landscape of HLA Risk Alleles in Primary Nephrotic Syndrome and Post Kidney Transplant Recurrence

> **NIH NIH U01** · DUKE UNIVERSITY · 2024 · $650,335

## Abstract

PROJECT SUMMARY
Nephrotic syndrome (NS) is a poorly understood immune-mediated kidney disease. In children, 80% of all cases
are steroid responsive and are referred to as steroid sensitive NS (SSNS), while the other 20% are steroid
resistant (SRNS). SRNS is a major cause of end-stage kidney disease requiring dialysis and kidney
transplantation; unfortunately, 60% of patients with SRNS will develop disease recurrence following transplant
and ultimately kidney allograft failure. We and others have demonstrated that variants in Human Leukocyte
Antigen (HLA) genes are associated with NS, signifying that defects in adaptive immunity, involving dysregulation
of both T and B lymphocytes, may be central to NS pathogenesis. While the association between HLA and NS
is strong, previous studies were carried out in small mono-ethnic cohorts using genome wide association chips
with limited coverage of the HLA genes, and variants uncovered account for a small fraction of NS risk. Therefore,
the precise HLA alleles/haplotypes associated with NS remain unknown. To enhance our understanding of NS,
we and others have enrolled over 3,700 multi-ethnic patients with primary, secondary, and post-transplant NS
from major multicenter kidney disease studies. We propose to perform state of the art next generation
sequencing (NGS) of the coding and non-coding regions of major HLA class I and II genes to determine the
relationship between variants in these genes and risk of NS, response to therapy, and disease recurrence
following kidney transplantation. Our overarching hypothesis is that certain HLA alleles/haplotypes
associated with NS can predict pattern of corticosteroid response in primary NS and the risk of disease
recurrence following kidney transplantation. We will test our hypothesis and evaluate potential molecular
mechanisms through the following aims: 1) Identify NS HLA risk alleles/haplotypes using high resolution HLA
NGS in a cohort of multi-ethnic patients and determine the relationship between genotypes and therapy
response, 2) Investigate the association between primary NS HLA risk alleles/haplotypes and secondary causes
of immune-mediated NS (IgA and membranous nephropathy), 3) Determine common structural and functional
motifs within NS HLA risk alleles/haplotypes and non-risk alleles by in-silico modeling and compare gene and
protein expression of these alleles in B lymphocytes and kidneys of patients with NS, and 4) Determine the ability
of known and novel NS HLA risk haplotypes to predict disease recurrence following kidney transplantation.
Significance: The studies proposed in this application will use cutting-edge NGS of major HLA genes to
identify the precise HLA alleles/haplotypes that are associated with NS, therapy response, and disease
recurrence following kidney transplantation. Understanding the intrinsic role of HLA variants and adaptive
immunity dysfunction in NS will lead to identification of novel pathways that are important in disease
patho...

## Key facts

- **NIH application ID:** 10848358
- **Project number:** 5U01AI152585-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Rasheed Adebayo Gbadegesin
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,335
- **Award type:** 5
- **Project period:** 2020-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848358

## Citation

> US National Institutes of Health, RePORTER application 10848358, Defining the Landscape of HLA Risk Alleles in Primary Nephrotic Syndrome and Post Kidney Transplant Recurrence (5U01AI152585-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848358. Licensed CC0.

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