Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine.

TitreCommon variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine.
Publication TypeJournal Article
Year of Publication2017
AuthorsCorre, T, Olinger, E, Harris, SE, Traglia, M, Ulivi, S, Lenarduzzi, S, Belge, H, Youhanna, S, Tokonami, N, Bonny, O, Houillier, P, Polasek, O, Deary, IJ, Starr, JM, Toniolo, D, Gasparini, P, Vollenweider, P, Hayward, C, Bochud, M, Devuyst, O
JournalPflugers Archiv : European journal of physiology
Volume469
Issue1
Pagination91-103
Date Published01/2017
DOI10.1007/s00424-016-1913-7
Type of Articlereview
ISBN Number1432-2013 (ISSN Electronic) 0031-6768 (linking)
Mots-clésAnimals, Calcium/metabolism, Calcium/urine, Claudin-14, Claudins/genetics, GWAS, Humans, Kidney Tubules/metabolism, Magnesium/metabolism, Magnesium/urine, Mg/Ca ratio, polymorphism, Single Nucleotide/genetics, Tubular functions, Urine/chemistry
Abstract

The nature and importance of genetic factors regulating the differential handling of Ca(2+) and Mg(2+) by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10(-12)), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg(2+) over Ca(2+) in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.

Notes

Publication types: Review ; Journal ArticlePublication Status: ppublish

First publication date (online)

12/2016

WOS ID (UT)

000391373900010

Citation Key / SERVAL ID7514
Peer reviewRefereed

                         

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