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

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; ... (2018). Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes. Journal of the American Society of Nephrology : JASN, 29(1), pp. 335-348. American Society of Nephrology 10.1681/ASN.2017030267

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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.

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