|Beitragstitel||Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes|
Magnesium (Mg2+) homeostasis is critical for metabolism. The genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and their potential influence on metabolic traits in the general population are unknown.
Plasma and urine parameters were obtained of 9,099 individuals from seven cohorts for the first genome-wide meta-analysis of Mg2+ homeostasis. Two novel loci, TRPM6 (rs3824347, P=4.4×10-13) and ARL15 (rs35929, P=2.1×10-11), for urinary Mg2+ (uMg) were identified, accounting together for 2.3% of the variation in 24-h uMg excretion.
In human kidney cells, ARL15 was shown to regulate TRPM6-mediated currents. In zebrafish, the expression of the highly conserved ARL15 orthologue, arl15b, was regulated by dietary Mg2+ and arl15b-knockdown resulted in renal Mg2+ wasting and metabolic disturbances. The association of uMg with fasting insulin and fat mass was modified by ARL15 rs35929 in a general population. These studies uncover a novel gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.