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

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 nephro...

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Vydané v:	Nature communications Ročník 10; číslo 1; s. 5175 - 10
Hlavní autori:	Howles, Sarah A., Wiberg, Akira, Goldsworthy, Michelle, Bayliss, Asha L., Gluck, Anna K., Ng, Michael, Grout, Emily, Tanikawa, Chizu, Kamatani, Yoichiro, Terao, Chikashi, Takahashi, Atsushi, Kubo, Michiaki, Matsuda, Koichi, Thakker, Rajesh V., Turney, Benjamin W., Furniss, Dominic
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 15.11.2019 Nature Publishing Group Nature Portfolio
Predmet:	13/95 45 631/208/205/2138 631/443/810 631/80/86/1999 692/4022/1585/273 Adult Aged Asian People - genetics Calciferol Calcium Calcium (blood) Calcium (urinary) Calcium - metabolism Calcium ions Calcium oxalate Calcium signalling Calcium-sensing receptors Calculi Diacylglycerol Kinase - genetics Diacylglycerol Kinase - metabolism Dietary supplements Excretion Female Genetic diversity Genetic variance Genetic Variation Genome-wide association studies Genome-Wide Association Study Genomes Genotype Genotypes Heritability Humanities and Social Sciences Humans Japan Kidney Calculi - genetics Kidney Calculi - metabolism Kidney stones Kidneys Loci Male Metabolism Middle Aged multidisciplinary Nephrolithiasis Oxalic acid Patients Polymorphism, Single Nucleotide Precision medicine Prospective Studies Proteins - genetics Proteins - metabolism Receptors, Calcium-Sensing - genetics Receptors, Calcium-Sensing - metabolism Science Signal transduction Signaling Supplements United Kingdom Vitamin D Vitamin D - metabolism White People - genetics United Kingdom Japan
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca 2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca 2+ concentration and excretion.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-13145-x