Genetic variants of calcium and vitamin D metabolism in renal stone disease
BAUS ePoster online library. Howles S. 06/24/19; 259461; P1-2
Dr. Sarah Howles
Dr. Sarah Howles
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Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a multifactorial etiology and heritability of ~45-60%. To identify common genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations.


GWAS and trans-ethnic meta-analysis of 12,123 kidney stone cases and 416,928 controls was performed. Genotype-phenotype correlations were established in a validation cohort of kidney stone patients. Biological pathways were studied in vitro in HEK293 cells.


Twenty loci associated with nephrolithiasis were identified, ten of which are novel. One such locus is associated with CYP24A1 and is predicted to affect vitamin D metabolism. Five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. The CYP24A1-associated locus, correlated with serum calcium concentration and number of kidney stone episodes in a validation cohort of nephrolithiasis patients. In addition, the DGKD-associated locus correlated with urinary calcium excretion in the validation cohort. Moreover, DGKD knockdown was shown to impair CaSR-signal transduction in vitro, an effect that was rectified by the calcimimetic cinacalcet, thereby supporting the role of DGKD in CaSR signaling.

Our study identified ten novel loci associated with kidney stone disease; six loci are predicted to influence calcium-sensing receptor and vitamin D metabolism pathways. These findings indicate that genotyping may help to 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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