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J Am Soc Nephrol. 2018 Jan;29(1):335-348. doi: 10.1681/ASN.2017030267. Epub 2017 Nov 1.

Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes.

Author information

1
Institute of Social and Preventive Medicine.
2
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
3
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
4
Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
5
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine.
6
Institute of Physiology, University of Zürich, Zurich, Switzerland.
7
Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
8
Centre for Cognitive Ageing and Cognitive Epidemiology.
9
Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK.
10
Department of Medical Genetics, Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico "Burlo Garofolo," Trieste, Italy.
11
Service of Nephrology and.
12
Service of Nephrology, University Hospital of Lausanne, Lausanne, Switzerland.
13
University Clinic for Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
14
Division of Cardiology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.
15
Faculty of Medicine, University of Split, Split, Croatia.
16
Usher Institute of Population Health Sciences and Informatics.
17
Department of Medicine, Internal Medicine, and.
18
Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
19
Department of Genetics, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
20
Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France.
21
Department of General Pediatrics, University Hospital Münster, Munster, Germany.
22
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy; and.
23
Department of Experimental Genetics, Sidra, Doha, Qatar.
24
Department of Psychology, and.
25
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, Scotland, UK.
26
Institute of Social and Preventive Medicine, olivier.devuyst@uzh.ch murielle.bochud@chuv.ch.
27
Institute of Physiology, University of Zürich, Zurich, Switzerland; olivier.devuyst@uzh.ch murielle.bochud@chuv.ch.

Abstract

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

KEYWORDS:

Gene-environment interaction; Genetic determinants; Magnesium homeostasis; Metabolic syndrome; Tubular transport; zebrafish

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