Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes.
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.
['Corre|Tanguy|T|', 'Arjona|Francisco J|FJ|', 'Hayward|Caroline|C|', 'Youhanna|Sonia|S|', 'de Baaij|Jeroen H F|JHF|', 'Belge|Hendrica|H|', 'Nägele|Nadine|N|', 'Debaix|Huguette|H|', 'Blanchard|Maxime G|MG|', 'Traglia|Michela|M|', 'Harris|Sarah E|SE|', 'Ulivi|Sheila|S|', 'Rueedi|Rico|R|', 'Lamparter|David|D|', 'Macé|Aurélien|A|', 'Sala|Cinzia|C|', 'Lenarduzzi|Stefania|S|', 'Ponte|Belen|B|', 'Pruijm|Menno|M|', 'Ackermann|Daniel|D|', 'Ehret|Georg|G|', 'Baptista|Daniela|D|', 'Polasek|Ozren|O|', 'Rudan|Igor|I|', 'Hurd|Toby W|TW|', 'Hastie|Nicholas D|ND|', 'Vitart|Veronique|V|', 'Waeber|Geràrd|G|', 'Kutalik|Zoltán|Z|', 'Bergmann|Sven|S|', 'Vargas-Poussou|Rosa|R|', 'Konrad|Martin|M|', 'Gasparini|Paolo|P|', 'Deary|Ian J|IJ|', 'Starr|John M|JM|', 'Toniolo|Daniela|D|', 'Vollenweider|Peter|P|', 'Hoenderop|Joost G J|JGJ|', 'Bindels|René J M|RJM|', 'Bochud|Murielle|M|', 'Devuyst|Olivier|O|']
D020727:ADP-Ribosylation Factors D050154:Adiposity D000818:Animals D019204:GTP-Binding Proteins D059647:Gene-Environment Interaction D055106:Genome-Wide Association Study D006706:Homeostasis D006801:Humans D007328:Insulin D007333:Insulin Resistance D007668:Kidney D008274:Magnesium D051379:Mice D009765:Obesity D010641:Phenotype D020641:Polymorphism, Single Nucleotide D012333:RNA, Messenger D050053:TRPM Cation Channels D015027:Zebrafish D029961:Zebrafish Proteins
Magnesium homeostasis Genetic determinants zebrafish Gene-environment interaction Metabolic syndrome Tubular transport