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

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.
Authors	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 (Nat Commun) Vol. 10 Issue 1 Pg. 5175 (11 15 2019) ISSN: 2041-1723 [Electronic] England
PMID	31729369 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)
Chemical References	Proteins Receptors, Calcium-Sensing WDR72 protein, human Vitamin D DGKD protein, human Diacylglycerol Kinase Calcium
Topics	Adult Aged Asian People (genetics) Calcium (metabolism) Diacylglycerol Kinase (genetics, metabolism) Female Genetic Variation Genome-Wide Association Study Genotype Humans Japan Kidney Calculi (genetics, metabolism) Male Middle Aged Polymorphism, Single Nucleotide Prospective Studies Proteins (genetics, metabolism) Receptors, Calcium-Sensing (genetics, metabolism) United Kingdom Vitamin D (metabolism) White People (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!