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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.

SUBMITTER: Howles SA

PROVIDER: S-EPMC6858460 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Howles Sarah A SA Wiberg Akira A Goldsworthy Michelle M Bayliss Asha L AL Gluck Anna K AK Ng Michael M Grout Emily E Tanikawa Chizu C Kamatani Yoichiro Y Terao Chikashi C Takahashi Atsushi A Kubo Michiaki M Matsuda Koichi K Thakker Rajesh V RV Turney Benjamin W BW Furniss Dominic D

Nature communications 20191115 1

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 infl ...[more]

PMID: 31729369

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Project description:Background and objectivePrevious studies have reported a strong genetic contribution to kidney stone risk. This study aims to identify genetic associations of kidney stone disease within a large-scale electronic health record system.MethodsWe performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5571 cases and 83 692 controls. This analysis included a primary GWAS focused on nephrolithiasis and subsequent subgroup GWASs stratified by stone composition types. For significant risk variants, we performed association analyses with stone composition and first-time 24-h urine parameters. To assess disease severity, we investigated the associations with age at first stone diagnosis, age at first stone-related procedure, and time between first and second stone-related procedures.Key findings and limitationsThe primary GWAS analysis identified ten significant loci, all located on chromosome 16 within coding regions of the UMOD gene. The strongest signal was rs28544423 (odds ratio 1.17, 95% confidence interval 1.11-1.23, p = 2.7 × 10-9). In subgroup GWASs stratified by six kidney stone composition subtypes, 19 significant loci were identified including two loci in coding regions (brushite; NXPH1, rs79970906 and rs4725104). The UMOD single nucleotide polymorphism rs28544423 was associated with differences in 24-h excretion of urinary analytes, and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p < 0.05). No associations were found between UMOD variants and disease severity. Limitations include an omitted variable bias and a misclassification bias.Conclusions and clinical implicationsWe replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-h urine parameters and stone composition, but not disease severity.Patient summaryWe identify genetic variants linked to kidney stone disease within an electronic health record (EHR) system. These findings suggest a role for the EHR to enable a precision-medicine approach for stone disease.

Dataset Information

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

Publications

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

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