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Genetic variants predisposing to increased risk of kidney stone disease
Open accessPreprint — published as 10.1172/jci186915 · Paper page
Abstract
Kidney stones (KS) are common, heritable, and associated with mineral metabolism abnormalities. We used Mendelian randomization and colocalization to identify variants predicted to increase KS risk via increased serum calcium or decreased serum phosphate (odds ratios for genomic regions=4.30-13.83 per 1 standard deviation alteration) that account for 11-19% of KS due to reduced calcium-sensing receptor (CaSR)-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation via diacylglycerol kinase delta ( DGKD ), solute carrier family 34 member 1 ( SLC34A1 ), and cytochrome P450 family 24 subfamily A member 1 ( CYP24A1 ), respectively. In silico analyses revealed that targeting CASR , DGKD , or CYP24A1 to decrease serum calcium, or SLC34A1 to increase serum phosphate may reduce KS risk, and in vitro studies demonstrated that positive CaSR-allosteric modulation ameliorates CaSR-signal transduction impaired by reduced DGKδ expression or KS-associated DGKD missense variants. These studies suggest that genotyping individuals with KS may facilitate personalized risk stratification and pharmacomodulation.
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Metadata
- Authors
- Lovegrove, C. E., Goldsworthy, M., Haley, J., Diane, S., Gorvin, C., Hannan, F. M., Mahajan, A., Mohnish, S., Sadeghi-Alavijeh, O., Moochhala, S., Gale, D., Carey, D., Holmes, M. V., Furniss, D., Thakker, R. V., & Howles, S. A.
- Affiliations
- University of Oxford (GB)
- Geisinger Medical Center (US)
- University of Birmingham (GB)
- Centre for Human Genetics (GB)
- The Royal Free Hospital (GB)
- University of Bristol (GB)
- Queen Mary University of London (GB)
- National Institute for Health and Care Research (GB)
- Corresponding author
- Lovegrove, Catherine E.
- Goldsworthy, Michelle
- Haley, Jeremy
- Gorvin, Caroline
- Hannan, Fadil M.
- Mahajan, Anubha
- Moochhala, Shabbir
- Gale, Daniel
- Carey, David
- Holmes, Michael V.
- Furniss, Dominic
- Thakker, Rajesh V.
- Howles, Sarah A.
- ORCID
- Venue
- Journal of Clinical Investigation
- Publisher
- openRxiv
- Published
- 2024-06-11
- Volume
- 135
- Issue
- 15
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC12321396
- OpenAlex
- W4410396916
- Cited by
- 18
- References
- 1
- Citations by year
- 2026: 12 · 2025: 6
- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (acceptedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Sanofi
- Alexion Pharmaceuticals
- Wellcome Trust (204826/Z/16/Z, 224155, 106995, 220668/Z/20/Z, NF-SI-0514-10091, 106995/Z/15/Z, 224155/Z/21/Z, 204826/z/16/z,106995/z/15/z, 10091, 204826)
- Cancer Research UK
- National Institute for Health and Care Research (NF-SI-0514-10091)
- Department of Health and Social Care
- Kidney Research UK (RP_030_20180306))
- St Peter’s Trust for Kidney Bladder and Prostate Research
- Novo Nordisk
- Urology Foundation
- Medical Research Council (MR/W03168X/1, MR/S021329/1)
- NIHR Oxford Biomedical Research Centre (NF-SI-0514-10091)
- Topics
- Health Sciences › Medicine › Urology › Kidney Stones and Urolithiasis Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- kidney stones, genetic susceptibility, calcium homeostasis, phosphate homeostasis, calcium-sensing receptor, SLC34A1, CYP24A1, 1,25-dihydroxyvitamin D, cinacalcet, urinary phosphate excretion, genetic loci, personalized risk stratification, Mendelian randomization
- MeSH terms
- Adult, Calcium, Female, Humans, Kidney Calculi, Male, Middle Aged, Phosphates, Signal Transduction, Genetic Predisposition to Disease, Receptors, Calcium-Sensing, Sodium-Phosphate Cotransporter Proteins, Type IIa, Genome-Wide Association Study, Mendelian Randomization Analysis
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