Kidney Stones are related to poor genes – example of CYP24A1 (Vitamin D) – Nov 2019

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

Nat Commun. 2019 Nov 15;10(1):5175. doi: 10.1038/s41467-019-13145-x.
Howles SA1,2, Wiberg A3, Goldsworthy M4,5, Bayliss AL5, Gluck AK5, Ng M3, Grout E4, Tanikawa C6, Kamatani Y7, Terao C7, Takahashi A7, Kubo M7, Matsuda K8, Thakker RV5, Turney BW4, Furniss D3.

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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.

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