Evaluation of Genetic Associations with Clinical Phenotypes of Kidney Stone Disease
From a large-scale electronic health record, we replicate kidney stone disease risk loci within UMOD (16p12.3). We demonstrate differences in stone composition and 24-h urine parameters consistent with uromodulin function as an inhibitor for calcium-based stone types. Previous studies have reported...
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Published in: | European urology open science (Online) Vol. 67; pp. 38 - 44 |
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Main Authors: | , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
Netherlands
Elsevier B.V
01-09-2024
Elsevier |
Subjects: | |
Online Access: | Get full text |
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Summary: | From a large-scale electronic health record, we replicate kidney stone disease risk loci within UMOD (16p12.3). We demonstrate differences in stone composition and 24-h urine parameters consistent with uromodulin function as an inhibitor for calcium-based stone types.
Previous studies have reported a strong genetic contribution to kidney stone risk. This study aims to identify genetic associations of kidney stone disease within a large-scale electronic health record system.
We performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5571 cases and 83 692 controls. This analysis included a primary GWAS focused on nephrolithiasis and subsequent subgroup GWASs stratified by stone composition types. For significant risk variants, we performed association analyses with stone composition and first-time 24-h urine parameters. To assess disease severity, we investigated the associations with age at first stone diagnosis, age at first stone-related procedure, and time between first and second stone-related procedures.
The primary GWAS analysis identified ten significant loci, all located on chromosome 16 within coding regions of the UMOD gene. The strongest signal was rs28544423 (odds ratio 1.17, 95% confidence interval 1.11–1.23, p = 2.7 × 10–9). In subgroup GWASs stratified by six kidney stone composition subtypes, 19 significant loci were identified including two loci in coding regions (brushite; NXPH1, rs79970906 and rs4725104). The UMOD single nucleotide polymorphism rs28544423 was associated with differences in 24-h excretion of urinary analytes, and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p < 0.05). No associations were found between UMOD variants and disease severity. Limitations include an omitted variable bias and a misclassification bias.
We replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-h urine parameters and stone composition, but not disease severity.
We identify genetic variants linked to kidney stone disease within an electronic health record (EHR) system. These findings suggest a role for the EHR to enable a precision-medicine approach for stone disease. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2666-1683 2666-1683 |
DOI: | 10.1016/j.euros.2024.07.109 |