Genome-wide meta-analysis unravels interactions between magnesium homeostasis and metabolic phenotypes

Tanguy Corre, Francisco J. Arjona, Caroline Hayward, Sonia Youhanna, Jeroen H.F. De Baaij, Hendrica Belge, Nadine Nägele, Huguette Debaix, Maxime G. Blanchard, Michela Traglia, Sarah E. Harris, Sheila Ulivi, Rico Rueedi, David Lamparter, Aurélien Macé, 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, Geràrd Waeber, Zoltán Kutalik, Sven Bergmann, Rosa Vargas-Poussou, Martin Konrad, Paolo Gasparini, Ian J. Deary, John M. Starr, Daniela Toniolo, Peter Vollenweider, Joost G.J. Hoenderop, René J.M. Bindels, Murielle Bochud, Olivier Devuyst

Research output: Contribution to journalArticle

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=4.4310213) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1310211), 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 (US)
Pages (from-to)335-348
Number of pages14
JournalJournal of the American Society of Nephrology
Volume29
Issue number1
DOIs
StatePublished - Jan 2018

ASJC Scopus subject areas

  • Nephrology

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    Corre, T., Arjona, F. J., Hayward, C., Youhanna, S., De Baaij, J. H. F., Belge, H., Nägele, N., Debaix, H., Blanchard, M. G., Traglia, M., Harris, S. E., Ulivi, S., Rueedi, R., Lamparter, D., Macé, A., Sala, C., Lenarduzzi, S., Ponte, B., Pruijm, M., ... Devuyst, O. (2018). Genome-wide meta-analysis unravels interactions between magnesium homeostasis and metabolic phenotypes. Journal of the American Society of Nephrology, 29(1), 335-348. https://doi.org/10.1681/ASN.2017030267