Institute of Social and Preventive Medicine.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
J Am Soc Nephrol. 2018 Jan;29(1):335-348. doi: 10.1681/ASN.2017030267. Epub 2017 Nov 1.
Magnesium (Mg) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg, which is crucial for Mg 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 Mg homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (4.4×10) near , which encodes an epithelial Mg channel, and rs35929 (2.1×10), a variant of , 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 Mg regulated the expression of the highly conserved ortholog , and knockdown resulted in renal Mg wasting and metabolic disturbances. Finally, 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 Mg deficiency to insulin resistance and obesity.
镁（Mg）稳态对代谢至关重要。然而，肾脏对 Mg 的处理的遗传决定因素对于 Mg 稳态至关重要，并且对普通人群的代谢特征的潜在影响尚不清楚。我们从七个队列中的 9099 个人中获得了血浆和尿液参数，并对 Mg 稳态进行了全基因组荟萃分析。我们鉴定了与尿镁（uMg）相关的两个位点，rs3824347（4.4×10）位于编码上皮 Mg 通道的附近，以及 rs35929（2.1×10），是编码 GTP 结合蛋白的 的变体。这些位点共同解释了 24 小时 uMg 排泄变异的 2.3%。在人类肾细胞中，ARL15 调节 TRPM6 介导的电流。在斑马鱼中，饮食镁调节高度保守的 直系同源物的表达，并且 敲低导致肾脏镁浪费和代谢紊乱。最后，rs35929 改变了 uMg 与空腹胰岛素和脂肪量在普通人群中的关联。总之，这种结合观察和实验的方法揭示了一种基因-环境相互作用，将镁缺乏与胰岛素抵抗和肥胖联系起来。
