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

J Am Soc Nephrol. 2018 Jan;29(1):335-348. doi: 10.1681/ASN.2017030267. Epub 2017 Nov 1.

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.

Keywords: Gene-environment interaction; Genetic determinants; Magnesium homeostasis; Metabolic syndrome; Tubular transport; zebrafish.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics*
  • Adiposity / genetics
  • Animals
  • GTP-Binding Proteins / genetics
  • 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
  • Zebrafish Proteins / genetics

Substances

  • Insulin
  • RNA, Messenger
  • TRPM Cation Channels
  • TRPM6 protein, human
  • Trpm6 protein, mouse
  • Zebrafish Proteins
  • arl15a protein, zebrafish
  • arl15b protein, zebrafish
  • GTP-Binding Proteins
  • ADP-Ribosylation Factors
  • ARL15 protein, human
  • ARL15 protein, mouse
  • Magnesium