Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes

Tanguy Corre, Francisco J Arjona, Caroline Hayward, Sonia Youhanna, Jeroen de Baaij, Hendrica Belge, Nadine Nagele, Huguette Debaix, Maxime G Blanchard, Michela Traglia, Sarah Harris, Sheila Ulivi, Rico Rueedi, David Lamparter, Aurelien Mace, Cinzia Sala, Stefania Lenarduzzi, Belen Ponte, Menno Pruijm, Daniel AckermannGeorg Ehret, Daniela Baptista, Ozren Polasek, Igor Rudan, Toby W. Hurd, Nicholas D. Hastie, Veronique Vitart, Gerard Waeber, Zoltán Kutalik, S. Bergmann, Rosa Vargas-Poussou, Martin Konrad, Paolo Gasparini, Ian Deary, John Starr, Daniela Toniolo, P. Vollenweider, Joost G J Hoenderop, Rene J M Bindels, Murielle Bochud, Olivier Devuyst

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
JournalJournal of the American Society of Nephrology
Early online date1 Nov 2017
DOIs
Publication statusPublished - Jan 2018

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