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

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 Kubo, Koichi Matsuda, Rajesh V Thakker, Benjamin W Turney, Dominic Furniss

Journal: Nature communications 2020;10(1):5175

PMID: 31729369

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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.

Address: Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. [email protected].; Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. [email protected].; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.; Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.; Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.; Laboratory of Genome Technology, Human Genome Centre, University of Tokyo, Tokyo, Japan.; RIKEN Centre for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.; Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, University of Tokyo, Tokyo, Japan.

DOI: 10.1038/s41467-019-13145-x

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MeSH Terms: Adult, Aged, Asian People, Calcium, Diacylglycerol Kinase, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Japan, Kidney Calculi, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Proteins, Receptors, Calcium-Sensing, United Kingdom, Vitamin D, White People