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

Author:

Howles Sarah A.ORCID,Wiberg AkiraORCID,Goldsworthy MichelleORCID,Bayliss Asha L.,Gluck Anna K.ORCID,Ng MichaelORCID,Grout Emily,Tanikawa Chizu,Kamatani YoichiroORCID,Terao ChikashiORCID,Takahashi AtsushiORCID,Kubo Michiaki,Matsuda KoichiORCID,Thakker Rajesh V.ORCID,Turney Benjamin W.,Furniss DominicORCID

Abstract

AbstractKidney 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.

Funder

Kidney Research UK

Wellcome Trust

DH | National Institute for Health Research

RCUK | Medical Research Council

Oxford Biomedical Research Centre

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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