Author:
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
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.
Publisher
American Society of Nephrology (ASN)
Subject
Nephrology,General Medicine
Cited by
33 articles.
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