title: Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine.
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.
authors.affiliation: Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.|Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Corre
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Olinger
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Traglia
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Sheila
authors.initials: S
authors.lastname: Ulivi
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lenarduzzi
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Hendrica
authors.initials: H
authors.lastname: Belge
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Youhanna
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tokonami
authors.affiliation: Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.affiliation: INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.|Département de Physiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.affiliation: Faculty of Medicine, University of Split, Split, Croatia.|Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.affiliation: Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.|Department of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: MRC IGMM, University of Edinburgh, Edinburgh, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland. olivier.devuyst@uzh.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000652:urine*; D057167:Claudins / Q000235:genetics*; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism / Q000652:urine*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014556:Urine / Q000737:chemistry*
chemical_list: D057167:Claudins; D008274:Magnesium; D002118:Calcium; C422064:claudin 14
keywords: Claudin-14; GWAS; Mg/Ca ratio; Tubular functions