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

Sarah A. Howles D.Phil., F.R.C.S.(Urol), Akira Wiberg B.M.B.Ch., Michelle Goldsworthy Ph.D., Asha L. Bayliss Ph.D., Emily Grout R.G.N., Chizu Tanikawa Ph.D., Yoichiro Kamatani M.D., Ph.D., Chikashi Terao M.D., Ph.D., Atsushi Takahashi Ph.D., Michiaki Kubo M.D., Ph.D., Koichi Matsuda M.D., Ph.D., Rajesh V. Thakker M.D., F.R.C.P., F.R.S., Benjamin W. Turney D.Phil., F.R.C.S.(Urol), and Dominic Furniss D.M., F.R.C.S.(Plast).

Feb 05, 2019

Received Date: 28th January 19

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden1,2 with a heritability of ~45-60>#sup###3. To identify genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations, including 12,123 nephrolithiasis cases and 416,928 controls. Twenty loci associated with nephrolithiasis were identified, ten of which are novel. A novel 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 nephrolithiasis patients the CYP24A1-associated locus correlated with serum calcium concentration and number of kidney stone episodes, and the DGKD-associated locus correlated with urinary calcium excretion. Moreover, DGKD knockdown impaired CaSR-signal transduction in vitro, an effect that was rectifiable with the calcimimetic cinacalcet. Our findings indicate that genotyping may inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR-signaling or vitamin D activation pathways in patients with recurrent kidney stones.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature