Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 29, Issue 1, Pages 335-348Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2017030267
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Funding
- Long-Term Fellowship from the European Renal Association European Dialysis and Transplant Association [ERA LTF 175-2014]
- Impulsion Grant from the ERA-EDTAWorking Group on Inherited Kidney Disorders
- Netherlands Organization for Scientific Research (NWO) [VICI 016.130.668]
- NWO [Rubicon 825.14.021]
- EURenOmics project from the European Union Seventh Framework Programme (FP7) [305608]
- Leenaards Foundation
- Swiss National Science Foundation [31003A-143914, 31003A_169850, FN 33CM30-124087, 33CSCO-122661, 33CS30-139468, 33CS30-148401]
- SystemsX.ch [51RTP0_151019]
- Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney)
- European Community's Seventh Framework Programme [305608 EURenOmics]
- Rare Disease Initiative Zurich (radiz), a clinical research priority program of the University of Zurich, Switzerland
- GlaxoSmithKline
- Faculty of Biology and Medicine of Lausanne, Lausanne University
- Medical Research Council (UK)
- European Commission Framework six-project EUROSPAN (European Special Populations Research Network) [LSHG-CT-2006-018947]
- Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]
- Compagnia di San Paolo, Torino, Italy
- Fondazione Cariplo, Italy
- Ministry of Health, Ricerca Finalizzata
- Age UK (The Disconnected Mind project)
- BBSRC (Biotechnology and Biological Sciences Research Council) [BB/F019394/1]
- University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the crosscouncil Lifelong Health and Wellbeing Initiative [MR/K026992/1]
- BBSRC
- Medical Research Council
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- Medical Research Council [MR/K026992/1, G0700704B, MC_PC_U127561128, MC_UU_00007/10] Funding Source: researchfish
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [MC_UU_00007/10, MC_PC_U127561128] Funding Source: UKRI
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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=4.4x10(-13)) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1x10(-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.
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