Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities.
Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using genome-wide association analyses, region-specific Mendelian randomization (MR), and genetic colocalization. Utility of pathway modulation was estimated via drug-target MR, and effects of variants on calcium-sensing receptor (CaSR)-signaling characterized.
Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified three loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration; p<5.6x10-10). Colocalization analyses defined putative, non-coding KSD-causing variants estimated to account for 11-19% of KSD cases in proximity to diacylglycerol kinase delta (DGKD), a CaSR-signalling 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 0.08mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16mmol/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.
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 personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.
The Journal of clinical investigation. 2025 May 15 [Epub ahead of print]
Catherine E Lovegrove, Michelle Goldsworthy, Jeremy Haley, Diane Smelser, Caroline Gorvin, Fadil M Hannan, Anubha Mahajan, Mohnish Suri, Omid Sadeghi-Alavijeh, Shabbir H Moochhala, Daniel P Gale, David Carey, Michael V Holmes, Dominic Furniss, Rajesh V Thakker, Sarah A Howles
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom., Department of Genomic Health, Geisinger Medical Center, Danville, United States of America., Institute of Metabolism and Systems Research and Centre of Membrane Protein, University of Birmingham, Birmingham, United Kingdom., Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom., Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom., Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom., UCL Department of Renal Medicine, University College London, London, United Kingdom., Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom., Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Scien, University of Oxford, Oxford, United Kingdom., Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.