TY - JOUR
T1 - Genome-wide meta-analysis unravels interactions between magnesium homeostasis and metabolic phenotypes
AU - Corre, Tanguy
AU - Arjona, Francisco J.
AU - Hayward, Caroline
AU - Youhanna, Sonia
AU - De Baaij, Jeroen H.F.
AU - Belge, Hendrica
AU - Nägele, Nadine
AU - Debaix, Huguette
AU - Blanchard, Maxime G.
AU - Traglia, Michela
AU - Harris, Sarah E.
AU - Ulivi, Sheila
AU - Rueedi, Rico
AU - Lamparter, David
AU - Macé, Aurélien
AU - Sala, Cinzia
AU - Lenarduzzi, Stefania
AU - Ponte, Belen
AU - Pruijm, Menno
AU - Ackermann, Daniel
AU - Ehret, Georg
AU - Baptista, Daniela
AU - Polasek, Ozren
AU - Rudan, Igor
AU - Hurd, Toby W.
AU - Hastie, Nicholas D.
AU - Vitart, Veronique
AU - Waeber, Geràrd
AU - Kutalik, Zoltán
AU - Bergmann, Sven
AU - Vargas-Poussou, Rosa
AU - Konrad, Martin
AU - Gasparini, Paolo
AU - Deary, Ian J.
AU - Starr, John M.
AU - Toniolo, Daniela
AU - Vollenweider, Peter
AU - Hoenderop, Joost G.J.
AU - Bindels, René J.M.
AU - Bochud, Murielle
AU - Devuyst, Olivier
N1 - Funding Information:
This work was supported by the Long-Term Fellowship from the European Renal Association European Dialysis and Transplant Association (ERA LTF 175-2014) and the Impulsion Grant from the ERA-EDTA Working Group on Inherited Kidney Disorders to F.J.A; and by the grant from The Netherlands Organization for Scientific Research (NWO; VICI 016.130.668) to J.G.J.H. J.H.F.d.B. is supported byagrant from NWO (Rubicon 825.14.021) andR.J.M.B.is supported by the EURenOmics project from the European Union Seventh Framework Programme (FP7/2007–2013, agreement no 305608). Z.K. received financial support from the Leenaards Foundation, the Swiss National Science Foundation (31003A-143914), and SystemsX. ch (51RTP0_151019). M.B. and T.C. are supported by the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.C.H.) program. O.D. is supported by the European Community’s Seventh Framework Programme (305608 EURenOmics), the Swiss National Centre of Competence in Research Kidney Control of Homeostasis (NCCR Kidney.C.H.) program, the Swiss National Science Foundation (31003A_169850), and the Rare Disease Initiative Zurich (radiz), a clinical research priority program of the University of Zurich, Switzerland. The SKIPOGH (Swiss Kidney Project on Genes in Hypertension) study is supported by a grant from the Swiss National Science Foundation (FN 33CM30-124087). The CoLaus (Cohorte Lausannoise) study is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, Lausanne University, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). The CROATIA-Korcula and CROATIA-Split studies were funded by grants from the Medical Research Council (UK), European Commission Framework six-project EUROSPAN (European Special Populations Research Network) (contract no. LSHG-CT-2006-018947), and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). For the INGI-Val Borbera study, the research was supported by funds from Compagnia di San Paolo, Torino, Italy; Fondazione Cariplo, Italy; and Ministry of Health, Ricerca Finalizzata 2008 to D.T. Phenotype collection in LBC1936 was supported by Age UK (The Disconnected Mind project). Genotyping was funded by the BBSRC (Biotechnology and Biological Sciences Research Council) (BB/ F019394/1). The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the crosscouncil Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council is gratefully acknowledged.
Publisher Copyright:
Copyright © 2018 by the American Society of Nephrology.
PY - 2018/1
Y1 - 2018/1
N2 - 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=4.4310213) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1310211), 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.
AB - 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=4.4310213) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1310211), 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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U2 - 10.1681/ASN.2017030267
DO - 10.1681/ASN.2017030267
M3 - Article
C2 - 29093028
AN - SCOPUS:85040122816
SN - 1046-6673
VL - 29
SP - 335
EP - 348
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 1
ER -