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

Author

Listed:
  • Sarah A. Howles

    (University of Oxford
    University of Oxford)

  • Akira Wiberg

    (University of Oxford)

  • Michelle Goldsworthy

    (University of Oxford
    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)

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.

Suggested Citation

  • 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 , 2019. "Genetic variants of calcium and vitamin D metabolism in kidney stone disease," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13145-x
    DOI: 10.1038/s41467-019-13145-x
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    Cited by:

    1. Xingjie Hao & Zhonghe Shao & Ning Zhang & Minghui Jiang & Xi Cao & Si Li & Yunlong Guan & Chaolong Wang, 2023. "Integrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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