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

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 (<i>P=</i>4.4×10^-13) near <i>TRPM6</i>, which encodes an epithelial Mg²⁺ channel, and rs35929 (<i>P=</i>2.1×10^-11), a variant of <i>ARL15</i>, 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 <i>ARL15</i> ortholog <i>arl15b</i>, and <i>arl15b</i> knockdown resulted in renal Mg²⁺ wasting and metabolic disturbances. Finally, <i>ARL15</i> 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.