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, Dominic Furniss

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number5175
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 01-12-2019

Fingerprint

kidney stones
calciferol
Calcium-Sensing Receptors
Nephrolithiasis
Kidney Calculi
Kidney Diseases
metabolism
loci
Metabolism
Vitamin D
calcium
Calcium
Signal transduction
Precision Medicine
Medicine
Genome-Wide Association Study
Genes
Chemical activation
excretion
Health

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Howles, S. A., Wiberg, A., Goldsworthy, M., Bayliss, A. L., Gluck, A. K., Ng, M., ... Furniss, D. (2019). Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nature Communications, 10(1), [5175]. https://doi.org/10.1038/s41467-019-13145-x
Howles, Sarah A. ; Wiberg, Akira ; Goldsworthy, Michelle ; Bayliss, Asha L. ; Gluck, Anna K. ; Ng, Michael ; Grout, Emily ; Tanikawa, Chizu ; Kamatani, Yoichiro ; Terao, Chikashi ; Takahashi, Atsushi ; Kubo, Michiaki ; Matsuda, Koichi ; Thakker, Rajesh V. ; Turney, Benjamin W. ; Furniss, Dominic. / Genetic variants of calcium and vitamin D metabolism in kidney stone disease. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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Howles, SA, Wiberg, A, Goldsworthy, M, Bayliss, AL, Gluck, AK, Ng, M, Grout, E, Tanikawa, C, Kamatani, Y, Terao, C, Takahashi, A, Kubo, M, Matsuda, K, Thakker, RV, Turney, BW & Furniss, D 2019, 'Genetic variants of calcium and vitamin D metabolism in kidney stone disease', Nature Communications, vol. 10, no. 1, 5175. https://doi.org/10.1038/s41467-019-13145-x

Genetic variants of calcium and vitamin D metabolism in kidney stone disease. / Howles, Sarah A.; Wiberg, Akira; Goldsworthy, Michelle; Bayliss, Asha L.; Gluck, Anna K.; Ng, Michael; Grout, Emily; Tanikawa, Chizu; Kamatani, Yoichiro; Terao, Chikashi; Takahashi, Atsushi; Kubo, Michiaki; Matsuda, Koichi; Thakker, Rajesh V.; Turney, Benjamin W.; Furniss, Dominic.

In: Nature Communications, Vol. 10, No. 1, 5175, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Kamatani, Yoichiro

AU - Terao, Chikashi

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Matsuda, Koichi

AU - Thakker, Rajesh V.

AU - Turney, Benjamin W.

AU - Furniss, Dominic

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Howles SA, Wiberg A, Goldsworthy M, Bayliss AL, Gluck AK, Ng M et al. Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nature Communications. 2019 Dec 1;10(1). 5175. https://doi.org/10.1038/s41467-019-13145-x