Genetic variants predisposing to increased risk of kidney stone disease.
Lovegrove CE., Goldsworthy M., Haley J., Smelser D., Gorvin C., Hannan FM., Mahajan A., Suri M., Sadeghi-Alavijeh O., Moochhala SH., Gale DP., Carey D., Holmes MV., Furniss D., Thakker RV., Howles SA.
BACKGROUND: Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities. METHODS: 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. RESULTS: 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. 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 personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.