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

Tanguy Corre, Eric Olinger, Sarah E. Harris, Michela Traglia, Sheila Ulivi, Stefania Lenarduzzi, Hendrica Belge, Sonia Youhanna, Natsuko Tokonami, Olivier Bonny, Pascal Houillier, Ozren Polasek, Ian J. Deary, John M. Starr, Daniela Toniolo, Paolo Gasparini, Peter Vollenweider, Caroline Hayward, Murielle Bochud, Olivier Devuyst

Research output: Contribution to journalArticle

Abstract

Abstract: The nature and importance of genetic factors regulating the differential handling of Ca2+ and Mg2+ 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 Mg2+ over Ca2+ 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.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalPflugers Archiv European Journal of Physiology
DOIs
Publication statusAccepted/In press - Dec 3 2016

Keywords

  • Claudin-14
  • GWAS
  • Mg/Ca ratio
  • Tubular functions

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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    Corre, T., Olinger, E., Harris, S. E., Traglia, M., Ulivi, S., Lenarduzzi, S., Belge, H., Youhanna, S., Tokonami, N., Bonny, O., Houillier, P., Polasek, O., Deary, I. J., Starr, J. M., Toniolo, D., Gasparini, P., Vollenweider, P., Hayward, C., Bochud, M., & Devuyst, O. (Accepted/In press). Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine. Pflugers Archiv European Journal of Physiology, 1-13. https://doi.org/10.1007/s00424-016-1913-7