TY - JOUR T1 - Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine. JF - Pflugers Arch Y1 - 2017 A1 - Corre, Tanguy A1 - Olinger, Eric A1 - Harris, Sarah E A1 - Traglia, Michela A1 - Ulivi, Sheila A1 - Lenarduzzi, Stefania A1 - Belge, Hendrica A1 - Youhanna, Sonia A1 - Tokonami, Natsuko A1 - Bonny, Olivier A1 - Houillier, Pascal A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Starr, John M A1 - Toniolo, Daniela A1 - Gasparini, Paolo A1 - Vollenweider, Peter A1 - Hayward, Caroline A1 - Bochud, Murielle A1 - Devuyst, Olivier KW - Animals KW - Calcium KW - Claudins KW - Humans KW - Kidney Tubules KW - Magnesium KW - Polymorphism, Single Nucleotide KW - Urine AB -

The nature and importance of genetic factors regulating the differential handling of Ca and Mg 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), 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 over Ca 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.

VL - 469 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27915449?dopt=Abstract ER -