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

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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.

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Acknowledgements

The CoLaus study is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). The computations for CoLaus imputation were performed in part at the Vital-IT Center for high performance computing of the Swiss Institute of Bioinformatics. MBO and TC are supported by the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.CH) program. OD is supported by grants from the European Community’s Seventh Framework Program (305608 EURenOmics), the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.CH) program, the Swiss National Science Foundation (310030-146490), and the Rare Disease Initiative Zurich (radiz), a clinical research priority program of the University of Zurich, Switzerland. EO is supported by the Fonds National de la Recherche Luxembourg (6903109) and the University Research Priority Program “Integrative Human Physiology, ZIHP” of the University of Zurich. NT is supported by funding from Swiss National Science Foundation Early and Advanced PostdocMolibity Fellowship (P2LAP3_151782 and P300P3_158521).

The CROATIA-Korcula and CROATIA-Split studies were funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947), and Republic of Croatia Ministry of Science, Education, and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula and Split, the administrative teams in Croatia and Edinburgh, and the people of Korcula and Split.

The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. The SNP genotyping for the CROATIA-Split cohort was performed by AROS Applied Biotechnology, Aarhus, Denmark.

INGI-Carlantino: We thank Anna Morgan and Angela D’Eustacchio for technical support. We are very grateful to the municipal administrators for their collaboration on the project and for logistic support. We would like to thank all participants to this study.

For the INGI-VALBORBERA study, the research was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy; and Ministry of Health, Ricerca Finalizzata 2008 to DT.

Phenotype collection in the Lothian Birth Cohort 1936 (LBC1936) was supported by Age UK (The Disconnected Mind project). Genotyping was funded by the BBSRC (BB/F019394/1). The work was undertaken by The University of Edinburgh Centre for Cognitive Aging and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. We thank the LBC1936 participants, the LBC1936 team for data collection and collation, and the staff at the Wellcome Trust Clinical Research Facility for bio-sample collection and genotyping.

Other funding sources: European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement no. 246539 (Marie Curie) and grant no. 305608 (EURenOmics), the NCCR Kidney.CH program (Swiss National Science Foundation), the Gebert Rüf Stiftung (Project GRS-038/12), and the Swiss National Science Foundation 310030-146490.

The authors acknowledge Nadine Nägele and Julien Weber for their help with the Platform of Biochemical Analyses at the University of Zurich and thank Jianghui Hou for the anti-claudin-14 antibodies and François Seghers, Yvette Cnops and Sébastien Druart (UCL Brussels) for help with the Mg2+ diets.

Author information

Authors and Affiliations

  1. Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland

    Tanguy Corre & Murielle Bochud

  2. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland

    Tanguy Corre

  3. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Tanguy Corre

  4. Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland

    Eric Olinger, Hendrica Belge, Sonia Youhanna, Natsuko Tokonami & Olivier Devuyst

  5. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    Sarah E. Harris, Ian J. Deary & John M. Starr

  6. 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

    Sarah E. Harris

  7. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy

    Michela Traglia & Daniela Toniolo

  8. Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste, Italy

    Sheila Ulivi & Stefania Lenarduzzi

  9. Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland

    Olivier Bonny & Peter Vollenweider

  10. INSERM U1138, Centre de Recherche des Cordeliers, Paris, France

    Pascal Houillier

  11. Département de Physiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France

    Pascal Houillier

  12. Faculty of Medicine, University of Split, Split, Croatia

    Ozren Polasek

  13. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK

    Ozren Polasek

  14. Department of Psychology, University of Edinburgh, Edinburgh, UK

    Ian J. Deary

  15. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK

    John M. Starr

  16. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy

    Paolo Gasparini

  17. Department of Experimental Genetics, Sidra Medical and Research Center, Doha, Qatar

    Paolo Gasparini

  18. MRC IGMM, University of Edinburgh, Edinburgh, UK

    Caroline Hayward

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  1. Tanguy Corre
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  2. Eric Olinger
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  3. Sarah E. Harris
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  4. Michela Traglia
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  9. Natsuko Tokonami
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  13. Ian J. Deary
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  14. John M. Starr
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Corresponding author

Correspondence to Olivier Devuyst.

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The authors declare they have no conflict of interest.

Additional information

Tanguy Corre and Eric Olinger jointly contributed

Caroline Hayward, Murielle Bochud, and Olivier Devuyst jointly directed the study

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Corre, T., Olinger, E., Harris, S.E. et al. Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine. Pflugers Arch - Eur J Physiol 469, 91–103 (2017). https://doi.org/10.1007/s00424-016-1913-7

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  • DOI: https://doi.org/10.1007/s00424-016-1913-7

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