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

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., Ackermann, D., Ehret, G., Baptista, D., Polasek, O., Rudan, I., Hurd, T.W., Hastie, N.D., Vitart, V., Waeber, G., Kutalik, Z., Bergmann, S., Vargas-Poussou, R., Konrad, M., Gasparini, P., Deary, I.J., Starr, J.M., Toniolo, D., Vollenweider, P., Hoenderop, J.G.J., Bindels, R.J.M., Bochud, M., Devuyst, O.
Journal of the American Society of Nephrology : JASN   29(1): 335-348 (Journal)
Registered Authors
Arjona, F.J., Hastie, Nicholas D.
Gene-environment interaction, Genetic determinants, Magnesium homeostasis, Metabolic syndrome, Tubular transport, zebrafish
MeSH Terms
  • ADP-Ribosylation Factors/genetics*
  • Adiposity/genetics
  • Animals
  • Gene-Environment Interaction
  • Genome-Wide Association Study
  • Homeostasis/genetics*
  • Humans
  • Insulin/blood
  • Insulin Resistance/genetics
  • Kidney/metabolism*
  • Magnesium/administration & dosage
  • Magnesium/blood*
  • Magnesium/urine*
  • Mice
  • Obesity/genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • RNA, Messenger/metabolism
  • TRPM Cation Channels/genetics*
  • Zebrafish
29093028 Full text @ J. Am. Soc. Nephrol.
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes