Genetic variants predisposing to an increased risk of kidney stone disease
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
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
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Clinical Research and Public Health Endocrinology Genetics Nephrology

Genetic variants predisposing to an increased risk of kidney stone disease

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.

Authors

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

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Figure 5

Functional characterization of kidney stone–associated DGKδ variants.

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Functional characterization of kidney stone–associated DGKδ variants. (A...
(A) CaSR-mediated SRE and (B) NFAT-RE responses to changes in extracellular calcium concentration [Ca2+]e in HEK-CaSR-DGK cells stably transfected with WT or the kidney stone–associated variants I91V, H190Q, I221N, T319A, V464I, R900H, or R1181W. Transfection with kidney stone–associated DGKD variants led to a reduction in SRE and NFAT-RE responses compared with cells transfected with WT DGKD. (C) Effect of 100 nM cinacalcet (cin) treatment on SRE responses at 3.5 mM [Ca2+]e and (D) NFAT-RE responses at 10 mM [Ca2+]e in HEK-CaSR-DGK cells transfected with the kidney stone–associated variants. Treatment with cinacalcet increased SRE-mediated responses of all variants but had no effect on NFAT-RE responses except for cells transfected with the R900H variant. (E) CaSR-mediated SRE and (F) NFAT-RE responses to changes in [Ca2+]e in HEK-CaSR cells following DGKδ KD (red), which led to a reduction in SRE responses without a change in NFAT-RE responses, compared with WT (black). (G) Effect of 5 nM cinacalcet treatment on SRE responses at 3.5 mM [Ca2+]e in HEK-CaSR cells following DGKδ KD. Treatment with cinacalcet rectified impaired SRE-mediated responses. Mean fold change responses ± SEM are shown for 4 biologically independent experiments. A 2-way ANOVA with Dunnett’s correction for multiple comparisons was used to compare points on the dose response curve with reference to WT. These data provide evidence that KSD is associated with impaired CaSR signal transduction, which can be ameliorated with cinacalcet. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 versus WT.