Genetic variants of calcium and vitamin D metabolism in kidney stone disease

Sarah A. Howles (), Akira Wiberg, Michelle Goldsworthy, Asha L. Bayliss, Anna K. Gluck, Michael Ng, Emily Grout, Chizu Tanikawa, Yoichiro Kamatani, Chikashi Terao, Atsushi Takahashi, Michiaki Kubo, Koichi Matsuda, Rajesh V. Thakker, Benjamin W. Turney and Dominic Furniss
Additional contact information
Sarah A. Howles: University of Oxford
Akira Wiberg: University of Oxford
Michelle Goldsworthy: University of Oxford
Asha L. Bayliss: University of Oxford
Anna K. Gluck: University of Oxford
Michael Ng: University of Oxford
Emily Grout: University of Oxford
Chizu Tanikawa: University of Tokyo
Yoichiro Kamatani: RIKEN Centre for Integrative Medical Sciences
Chikashi Terao: RIKEN Centre for Integrative Medical Sciences
Atsushi Takahashi: RIKEN Centre for Integrative Medical Sciences
Michiaki Kubo: RIKEN Centre for Integrative Medical Sciences
Koichi Matsuda: University of Tokyo
Rajesh V. Thakker: University of Oxford
Benjamin W. Turney: University of Oxford
Dominic Furniss: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45–60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.

Date: 2019
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DOI: 10.1038/s41467-019-13145-x

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