Lovegrove, Catherine E;
Goldsworthy, Michelle;
Haley, Jeremy;
Smelser, Diane;
Gorvin, Caroline;
Hannan, Fadil M;
Mahajan, Anubha;
... Howles, Sarah A; + view all
(2025)
Genetic variants predisposing to an increased risk of kidney stone disease.
The Journal of Clinical Investigation
, 135
(15)
, Article e186915. 10.1172/JCI186915.
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Abstract
BACKGROUND: Kidney stone disease (KSD) affects approximately 10% of adults, is heritable, and is associated with mineral metabolic abnormalities.METHODS: Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using GWAS, region-specific Mendelian randomization (MR), and genetic colocalization. The utility of pathway modulation was estimated via drug target MR, and the effects of variants on calcium-sensing receptor (CaSR) signaling were characterized. RESULTS: Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified 3 loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (ORs for genomic regions = 4.30, 11.42, and 13.83 per 1 SD alteration; P < 5.6 × 10-10). Colocalization analyses defined putative, noncoding KSD-causing variants estimated to account for 11%-19% of KSD cases in proximity to diacylglycerol kinase δ (DGKD), a CaSR signaling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug target MR indicated that reducing serum calcium by 0.08 mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16 mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR allosteric modulator. CONCLUSION: DGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalized KSD risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.FUNDING: Oxfordshire Health Services Research Committee (OHSRC, part of Oxford Hospitals Charity); Kidney Research UK (RP_030_20180306); The Urology Foundation; National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (NF-SI-0514-10091); Wellcome Trust (204826/z/16/z and 106995/z/15/z); Medical Research Council (MRC) Clinical Research Training Fellowships (MR/W03168X/1 and MR/S021329/1); Wellcome Trust Clinical Career Development Fellowship; Sir Henry Dale Fellowship, with joint funding by the Wellcome Trust and the Royal Society (224155/Z/21/Z); St. Peter's Trust for Kidney Bladder and Prostate Research.
Type: | Article |
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Title: | Genetic variants predisposing to an increased risk of kidney stone disease |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1172/JCI186915 |
Publisher version: | https://doi.org/10.1172/jci186915 |
Language: | English |
Additional information: | © 2025, Lovegrove et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/deed.en). |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine |
URI: | https://discovery.ucl.ac.uk/id/eprint/10212158 |
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