Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes

T Corre, FJ Arjona, C Hayward, S Youhanna, JHF de Baaij, H Belge, N Nägele, H Debaix, MG Blanchard, Michela Traglia, SE Harris, S Ulivi, R Rueedi, D Lamparter, A Macé, C Sala, S Lenarduzzi, B Ponte, M Pruijm, D AckermannG Ehret, D Baptista, O Polasek, I Rudan, TW Hurd, ND Hastie, V Vitart, G Waeber, Z Kutalik, S Bergmann, R Vargas-Poussou, M Konrad, P Gasparini, IJ Deary, JM Starr, D Toniolo, P Vollenweider, JGJ Hoenderop, RJM Bindels, M Bochud, O Devuyst

Research output: Contribution to journalArticle

Abstract

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. Copyright © 2018 by the American Society of Nephrology.
Original languageEnglish
Pages (from-to)335-348
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Volume29
Issue number1
DOIs
Publication statusPublished - 2018

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Magnesium
Meta-Analysis
Homeostasis
Genome
Phenotype
Kidney
Gene-Environment Interaction
Zebrafish
GTP-Binding Proteins
Population
Insulin Resistance
Fasting
Obesity
Fats
Urine
Insulin

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Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes. / Corre, T; Arjona, FJ; Hayward, C; Youhanna, S; de Baaij, JHF; Belge, H; Nägele, N; Debaix, H; Blanchard, MG; Traglia, Michela; Harris, SE; Ulivi, S; Rueedi, R; Lamparter, D; Macé, A; Sala, C; Lenarduzzi, S; Ponte, B; Pruijm, M; Ackermann, D; Ehret, G; Baptista, D; Polasek, O; Rudan, I; Hurd, TW; Hastie, ND; Vitart, V; Waeber, G; Kutalik, Z; Bergmann, S; Vargas-Poussou, R; Konrad, M; Gasparini, P; Deary, IJ; Starr, JM; Toniolo, D; Vollenweider, P; Hoenderop, JGJ; Bindels, RJM; Bochud, M; Devuyst, O.

In: Journal of the American Society of Nephrology : JASN, Vol. 29, No. 1, 2018, p. 335-348.

Research output: Contribution to journalArticle

Corre, T, Arjona, FJ, Hayward, C, Youhanna, S, de Baaij, JHF, Belge, H, Nägele, N, Debaix, H, Blanchard, MG, Traglia, M, Harris, SE, Ulivi, S, Rueedi, R, Lamparter, D, Macé, A, Sala, C, Lenarduzzi, S, Ponte, B, Pruijm, M, Ackermann, D, Ehret, G, Baptista, D, Polasek, O, Rudan, I, Hurd, TW, Hastie, ND, Vitart, V, Waeber, G, Kutalik, Z, Bergmann, S, Vargas-Poussou, R, Konrad, M, Gasparini, P, Deary, IJ, Starr, JM, Toniolo, D, Vollenweider, P, Hoenderop, JGJ, Bindels, RJM, Bochud, M & Devuyst, O 2018, 'Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes', Journal of the American Society of Nephrology : JASN, vol. 29, no. 1, pp. 335-348. https://doi.org/10.1681/ASN.2017030267
Corre, T ; Arjona, FJ ; Hayward, C ; Youhanna, S ; de Baaij, JHF ; Belge, H ; Nägele, N ; Debaix, H ; Blanchard, MG ; Traglia, Michela ; Harris, SE ; Ulivi, S ; Rueedi, R ; Lamparter, D ; Macé, A ; Sala, C ; Lenarduzzi, S ; Ponte, B ; Pruijm, M ; Ackermann, D ; Ehret, G ; Baptista, D ; Polasek, O ; Rudan, I ; Hurd, TW ; Hastie, ND ; Vitart, V ; Waeber, G ; Kutalik, Z ; Bergmann, S ; Vargas-Poussou, R ; Konrad, M ; Gasparini, P ; Deary, IJ ; Starr, JM ; Toniolo, D ; Vollenweider, P ; Hoenderop, JGJ ; Bindels, RJM ; Bochud, M ; Devuyst, O. / Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes. In: Journal of the American Society of Nephrology : JASN. 2018 ; Vol. 29, No. 1. pp. 335-348.
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abstract = "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. Copyright {\circledC} 2018 by the American Society of Nephrology.",
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T1 - Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes

AU - Corre, T

AU - Arjona, FJ

AU - Hayward, C

AU - Youhanna, S

AU - de Baaij, JHF

AU - Belge, H

AU - Nägele, N

AU - Debaix, H

AU - Blanchard, MG

AU - Traglia, Michela

AU - Harris, SE

AU - Ulivi, S

AU - Rueedi, R

AU - Lamparter, D

AU - Macé, A

AU - Sala, C

AU - Lenarduzzi, S

AU - Ponte, B

AU - Pruijm, M

AU - Ackermann, D

AU - Ehret, G

AU - Baptista, D

AU - Polasek, O

AU - Rudan, I

AU - Hurd, TW

AU - Hastie, ND

AU - Vitart, V

AU - Waeber, G

AU - Kutalik, Z

AU - Bergmann, S

AU - Vargas-Poussou, R

AU - Konrad, M

AU - Gasparini, P

AU - Deary, IJ

AU - Starr, JM

AU - Toniolo, D

AU - Vollenweider, P

AU - Hoenderop, JGJ

AU - Bindels, RJM

AU - Bochud, M

AU - Devuyst, O

PY - 2018

Y1 - 2018

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=4.4×10-13) 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. Copyright © 2018 by the American Society of Nephrology.

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=4.4×10-13) 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. Copyright © 2018 by the American Society of Nephrology.

U2 - 10.1681/ASN.2017030267

DO - 10.1681/ASN.2017030267

M3 - Article

VL - 29

SP - 335

EP - 348

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 1

ER -