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

Magnesium (Mg ) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg , which is crucial for Mg homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 indivi...

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Published in:Journal of the American Society of Nephrology Vol. 29; no. 1; p. 335
Main Authors: Corre, Tanguy, Arjona, Francisco J, Hayward, Caroline, Youhanna, Sonia, de Baaij, Jeroen H F, Belge, Hendrica, Nägele, Nadine, Debaix, Huguette, Blanchard, Maxime G, Traglia, Michela, Harris, Sarah E, Ulivi, Sheila, Rueedi, Rico, Lamparter, David, Macé, Aurélien, Sala, Cinzia, Lenarduzzi, Stefania, Ponte, Belen, Pruijm, Menno, Ackermann, Daniel, Ehret, Georg, Baptista, Daniela, Polasek, Ozren, Rudan, Igor, Hurd, Toby W, Hastie, Nicholas D, Vitart, Veronique, Waeber, Geràrd, Kutalik, Zoltán, Bergmann, Sven, Vargas-Poussou, Rosa, Konrad, Martin, Gasparini, Paolo, Deary, Ian J, Starr, John M, Toniolo, Daniela, Vollenweider, Peter, Hoenderop, Joost G J, Bindels, René J M, Bochud, Murielle, Devuyst, Olivier
Format: Journal Article
Language:English
Published: United States 01.01.2018
Subjects:
Adiposity - genetics
ADP-Ribosylation Factors - genetics
Animals
Gene-Environment Interaction
Genome-Wide Association Study
GTP-Binding Proteins - genetics
Homeostasis - genetics
Humans
Insulin - blood
Insulin Resistance - genetics
Kidney - metabolism
Magnesium - administration & dosage
Magnesium - blood
Magnesium - urine
Mice
Obesity - genetics
Phenotype
Polymorphism, Single Nucleotide
RNA, Messenger - metabolism
TRPM Cation Channels - genetics
Zebrafish
Zebrafish Proteins - genetics
Tubular transport
Genetic determinants
zebrafish
Metabolic syndrome
Gene-environment interaction
Magnesium homeostasis
ISSN:1533-3450, 1533-3450
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Summary:Magnesium (Mg ) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg , which is crucial for Mg 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 Mg homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 ( 4.4×10 ) near , which encodes an epithelial Mg channel, and rs35929 ( 2.1×10 ), a variant of , 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 Mg regulated the expression of the highly conserved ortholog , and knockdown resulted in renal Mg wasting and metabolic disturbances. Finally, 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 Mg deficiency to insulin resistance and obesity.
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ISSN:1533-3450
1533-3450
DOI:10.1681/ASN.2017030267