An individualized medicine approach to urinary stone disease

Active Project Grant Awarded Last action

Award ID
R01DK133171
Recipient
Awarding agency
Obligated
$4,075,861

Award facts

Completion date 47% complete
Originally
Place of performance
Rochester, MN 55905, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Urinary stone disease (USD) affects up to 12% of individuals in developed countries, and is associated with significant morbidity, pain, and annual US health care costs of >$10 billion. There is strong evidence of heritability, however risk factors remain relatively obscure. Our prior work in the rare kidney stone consortium (rksc) developed a targeted nephrology gene capture panel (tngs) with 144 known and candidate USD genes and resolved ~30% of >500 patients suspected of monogenic USD due to early onset nephrolithiasis (NL), nephrocalcinosis (NC), chronic kidney disease (CKD), and/or multiple stones, with ~15 different genes implicated. In addition to making a definitive diagnosis, in many cases the resulting information revealed new treatment options or directed patients to specific clinical trials. Here we propose extending our understanding of the spectrum of genes and variants associated with monogenic NL/NC in the rksc cohort, including functional in vitro analyses of variants of uncertain significance (VUS; aim #1). In parallel, we will study a cohort of >50,000 mayo clinic biobank patients with detailed linked medical record information (~12.7% with stones) (aim #2). Findings in this biobank cohort will be validated and extended in a prospective kidney stone cohort of more than 550 first time USD patients and 480 matched controls (aim #3). This third community-based cohort has detailed clinical and biochemical data, including comprehensive assessment of symptomatic and radiographic recurrence, and will thus allow detailed study of potential mechanism(s) of implicated genes. This proposal takes advantage of available genetic analyses in aim #2 and aim #3 that includes whole exome sequence (WES) as well as genomewide single nucleotide polymorphism (SNP) data for association studies. Studies will determine if coding, noncoding, and expression related variants of monogenic USD genes are associated with NL/NC risk and correlate with biochemical determinants of stones. Our specific aims are: aim #1: genotype patients suspected of monogenic forms of USD using global NGS approaches; aim #2: validate identified genetic USD risks in a mayo clinic biobank cohort including first time and recurrent calcium stone patients and controls with WES and SNP association studies; aim #3: characterize genetic USD risks and pathways in a prospective chart-validated cohort of first-time symptomatic calcium stone patients with age-SEX- matched controls with WES and SNP association studies. Our overall hypothesis is: variants in monogenic USD genes not only explain mendelian disease, but are risk factors for the common (predominately calcium) USD that is found in the general community. This study will improve understanding of the etiology and pathogenesis of monogenic USD and impact patient treatments and clinical trial recruitment. Risk factors for common US and its recurrence will also be identified.

Transactions

Action Obligated Date
Amendment $818,020
Amendment $0
Amendment $0
Amendment $0
Amendment $536,417
Amendment $514,961
Amendment $552,665
Amendment $551,266
Amendment $551,266
Original award $551,266

Subawards

Subrecipient Amount Awarded
Geisinger Clinic An individualized medicine approach to urinary stone disease $159,995

Quick answers

Who received award R01DK133171?

R01DK133171 was awarded to Mayo Clinic by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 1, 2022.

How much is award R01DK133171 worth?

$4,075,861 has been obligated on R01DK133171.

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