Work

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

Year: 2019

Type: review

Study design: Observational Study

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.

Source: Nature Communications

DOI: 10.1038/s41467-019-13145-x

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

Institutions: University of Oxford, The University of Tokyo, RIKEN Center for Integrative Medical Sciences

Language: English

Topic: Kidney Stones and Urolithiasis Treatments

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $5,200

Funders: Wellcome Trust, National Institute for Health and Care Research, Kidney Research UK, Medical Research Council, Japan Society for the Promotion of Science, NIHR Oxford Biomedical Research Centre

Awards: Identification of functional variants by comprehensive analysis of coding variants for the implementation of genomic medicine, Institutional Strategic Support Fund, G156387830, Calcium-sensing receptor (CaSR) - a G-protein coupled receptor (GPCR) - signalling pathways in health and disease., Suppression of radiation-induced gastrointestinal disorders through the regulation of intestinal flora by the tumor suppressor p53, G5251549192, NIHR Senior Investigator Award, Calcium-sensing receptor (CaSR) - a G-protein coupled receptor (GPCR) - signalling pathways in health and disease., G6504535377, G7235645904, Institutional Strategic Support Fund, The Genetic Architecture of Carpal Tunnel Syndrome, G990716275

OpenAlex ID: W2981815988

FWCI: 1.972

Cites: 72

Cited by: 147

Related to: 10