Sequence variants associating with urinary biomarkers

Benónísdóttir, Stefania; Kristjansson, Ragnar P.; Oddsson, Ásmundur; Steinthórsdóttir, Valgerður; Mikaelsdottir, Evgenia; Kehr, Birte; Jensson, Brynjar O.; Arnadottir, Gudny A.; Sulem, Gerald; Sveinbjörnsson, Garðar; Kristmundsdóttir, Snædís; Ívarsdóttir, Erna V.; Tragante, Vinicius; Gunnarsson, Bjarni; Runólfsdóttir, Hrafnhildur Linnet; Arthur, Joseph G.; Deaton, Aimée M.; Eyjolfsson, Gudmundur I.; Davidsson, Olafur B.; Asselbergs, Folkert W.; Hreiðarsson, Ástráður B.; Rafnar, Thorunn; Þorleifsson, Guðmar; Eðvarðsson, Viðar Örn; Sigurðsson, Gunnar; Helgadóttir, Anna; Halldórsson, Bjarni V.; Másson, Gísli; Hólm, Hilma; Önundarson, Páll T.; Indridason, Ólafur S.; Benediktsson, Rafn; Pálsson, Runólfur; Guðbjartsson, Daníel F.; Ólafsson, Ísleifur; Þorsteinsdóttir, Unnur; Sulem, Patrick; Stefánsson, Kāri

doi:10.1093/hmg/ddy409

Cited by 36 publications

(36 citation statements)

References 47 publications

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“…1) 11 . Seven of the identified loci have not previously been reported to associate with kidney stone disease at GWAS (Table 1) 8–11,15,16 . The allelic effects were concordant across both studies at all 20 loci, with minimal evidence of heterogeneity between the two GWAS at the majority of loci, with a Q-statistic p -value > 0.05 at 17 out of 20 loci (Supplementary Table 4), suggesting that the genetic architecture of kidney stone disease is very similar between populations of European and East Asian ancestry.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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“…GWASs have reported associations of renal stone disease with 25 loci (Box 2) 84,85,[142][143][144][145][146] . Three of these loci -CASR, CYP24A1, and SLC34A1 -are linked to genes implicated in monogenic disorders of nephrolithiasis [19][20][21]36,37,83,99,103 .…”

Section: [H2] Genome-wide Association Studiesmentioning

confidence: 99%

Genetics of kidney stone disease

2020

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Kidney stone disease (nephrolithiasis) is a common problem that can be associated with alterations in urinary solute composition including hypercalciuria. Studies suggest that the prevalence of monogenic kidney stone disorders, including renal tubular acidosis with deafness, Bartter syndrome, primary hyperoxaluria, and cystinuria, in patients attending kidney stone clinics is 15%. However, for the majority of individuals, nephrolithiasis has a multifactorial aetiology involving genetic and environmental factors. Nonetheless, the genetic influence on stone formation in these idiopathic stone formers remains considerable and twin studies estimate a heritability of >45% for nephrolithiasis and >50% for hypercalciuria. The contribution of polygenic influences from multiple loci have been investigated by genome-wide association and candidate gene studies, which indicate that a number of genes and molecular pathways contribute to the risk of stone formation. Genetic approaches, studying both monogenic and polygenic factors in nephrolithiasis, have revealed that the following have important roles in the aetiology of kidney stones: transporters and channels; ions, protons and amino acids; the calcium-sensing receptor (a G-protein-coupled receptor) signalling pathway; and the metabolic pathways for vitamin D, oxalate, cysteine, purines and uric acid. These advances, which have increased our understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of targeted therapies for precision medicine approaches in patients with nephrolithiasis.

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“…Patients display proteinuria [34], hypercalciuria, nephrocalcinosis, nephrolithiasis, and focal segmental glomerulosclerosis [35]. Genome-wide association studies confirmed the link between LRP2 and proteinuria [36]. Interestingly, patients with mutations in the genes encoding for OCRL1 (Lowe syndrome) and ClC-5 (Dent's disease) also display megalin dysfunction and proteinuria [37][38][39].…”

Section: Genetic Mutations Affecting Megalinmentioning

confidence: 99%

Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

Sun

Danser

2020

Curr Hypertens Rep

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Purpose of Review Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine. Recent Findings Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Summary Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin.

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Sequence variants associating with urinary biomarkers

Cited by 36 publications

References 47 publications

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

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

Genetics of kidney stone disease

Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

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