# Genetic and Functional Analysis of Rapid Renal Decline in Diabetes: A Family-based Approach to Accelerate Gene Discovery

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $656,449

## Abstract

PROJECT SUMMARY
 Diabetic nephropathy (DN) is a complex, heterogeneous complication of diabetes that is characterized by
progressive renal decline. While genetic factors are known to contribute to DN susceptibility, despite intense
effort, the identification of variants that underlie its risk has been challenging, largely due to the scarcity of well-
characterized cohorts designed to investigate the genetic basis of rapid renal decline. To overcome this
bottleneck, we’ve developed an innovative family-based approach to accelerate gene discovery in DN that
integrates unparalleled resources, including the Utah Diabetes Database (UDDb), which contains electronic
medical record data for more than 350,000 diabetic patients, the Utah Population Database, a unique
population-based genealogy resource containing family histories and demographic data for 14 million
individuals, and the Intermountain Biorepository, a large biorepository containing biospecimens for 147,000
patients in the UDDb. Using these resources, we’ve established one of the world’s largest and well-
characterized cohorts of diabetic patients with rapid progression of renal decline and identified >450 large,
multigenerational pedigrees enriched for this key feature of DN. As part of a recent pilot study applying our
approach, we identified putative disease-causing variants in 2 genes (ADIPOQ and FRAS1) not previously
known to contribute to DN. These strong preliminary findings highlight the power of family-based genetics to
discover novel genes that contribute to rapid renal decline and DN. We believe that these studies are just the
‘tip of the iceberg’ and that additional predisposing genes and pathways remain to be discovered. To further
advance this research, we will 1) define the pathophysiological mechanisms through which ADIPOQ and
FRAS1 affect rapid progression of renal decline in DN families by i) examining the role of ADIPOQ mutation on
renal decline and DN development using genetically edited mice (mice carrying the human mutation identified
in a high-risk pedigree have already been generated) and ii) examining the role of FRAS1 mutation on renal
decline and DN development using genetically edited mice. 2) Establish a comprehensive catalog of coding
variation in DN families enriched for rapid progression of renal decline by i) prioritizing high-risk pedigrees
enriched for rapid renal decline using innovative tools developed at the University of Utah and identifying select
individuals from these families to optimize WES-based gene discovery and ii) performing WES-based gene
discovery in newly identified high-risk pedigrees enriched for rapid renal decline. 3) Evaluate the causal
relationship between genetic variants identified in DN families enriched for rapid progression of renal decline
and rapid renal decline by i) prioritizing candidate genes discovered using WES to identify the most promising
candidates using statistical and biological evidence and ii) performing in vitro a...

## Key facts

- **NIH application ID:** 10186273
- **Project number:** 1R01DK128641-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Marcus Guy Pezzolesi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $656,449
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186273

## Citation

> US National Institutes of Health, RePORTER application 10186273, Genetic and Functional Analysis of Rapid Renal Decline in Diabetes: A Family-based Approach to Accelerate Gene Discovery (1R01DK128641-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10186273. Licensed CC0.

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