Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes

Tanguy Corre; Francisco J Arjona; Caroline Hayward; Sonia Youhanna; Jeroen de Baaij; Hendrica Belge; Nadine Nagele; Huguette Debaix; Maxime G Blanchard; Michela Traglia; Sarah Harris; Sheila Ulivi; Rico Rueedi; David Lamparter; Aurelien Mace; Cinzia Sala; Stefania Lenarduzzi; Belen Ponte; Menno Pruijm; Daniel Ackermann; Georg Ehret; Daniela Baptista; Ozren Polasek; Igor Rudan; Toby W. Hurd; Nicholas D. Hastie; Veronique Vitart; Gerard  Waeber; Zoltán Kutalik; S. Bergmann; Rosa Vargas-Poussou; Martin Konrad; Paolo Gasparini; Ian Deary; John Starr; Daniela Toniolo; P. Vollenweider; Joost G J Hoenderop; Rene J M Bindels; Murielle Bochud; Olivier Devuyst

doi:10.1681/ASN.2017030267

Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes

Tanguy Corre, Francisco J Arjona, Caroline Hayward, Sonia Youhanna, Jeroen de Baaij, Hendrica Belge, Nadine Nagele, Huguette Debaix, Maxime G Blanchard, Michela Traglia, Sarah Harris, Sheila Ulivi, Rico Rueedi, David Lamparter, Aurelien Mace, Cinzia Sala, Stefania Lenarduzzi, Belen Ponte, Menno Pruijm, Daniel AckermannGeorg Ehret, Daniela Baptista, Ozren Polasek, Igor Rudan, Toby W. Hurd, Nicholas D. Hastie, Veronique Vitart, Gerard Waeber, Zoltán Kutalik, S. Bergmann, Rosa Vargas-Poussou, Martin Konrad, Paolo Gasparini, Ian Deary, John Starr, Daniela Toniolo, P. Vollenweider, Joost G J Hoenderop, Rene J M Bindels, Murielle Bochud, Olivier Devuyst

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Journal of the American Society of Nephrology
Early online date	1 Nov 2017
DOIs	https://doi.org/10.1681/ASN.2017030267
Publication status	Published - Jan 2018

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10.1681/ASN.2017030267

Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes
This is the author's peer reviewed manuscript as accepted for publication.
Accepted author manuscript, 4.61 MB

HGU Core Award Apr 12 - MAr 18
Hastie, N., Adams, I., Baldock, R., Bickmore, W., Caceres, J., Dorin, J., FitzPatrick, D., Haley, C., Hill, B., Jackson, I., Jackson, A., Kudla, G., Meehan, R. & Patton, E.
MRC
1/04/12 → 31/03/18
Project: Research

Caroline Hayward
- Deanery of Molecular, Genetic and Population Health Sciences - UoE Retired Staff
- MRC Human Genetics Unit
Person: Academic: Research Active , Affiliated Independent Researcher
Toby Hurd
- Deanery of Molecular, Genetic and Population Health Sciences - Visitor: Default Visitor
Person: Affiliated Independent Researcher

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Corre, T., Arjona, F. J., Hayward, C., Youhanna, S., de Baaij, J., Belge, H., Nagele, N., Debaix, H., Blanchard, M. G., Traglia, M., Harris, S., Ulivi, S., Rueedi, R., Lamparter, D., Mace, A., Sala, C., Lenarduzzi, S., Ponte, B., Pruijm, M., ... Devuyst, O. (2018). Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes. Journal of the American Society of Nephrology. https://doi.org/10.1681/ASN.2017030267

@article{f9b6f6ba70524f03a118da6c087fe581,

title = "Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes",

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. ",

author = "Tanguy Corre and Arjona, {Francisco J} and Caroline Hayward and Sonia Youhanna and {de Baaij}, Jeroen and Hendrica Belge and Nadine Nagele and Huguette Debaix and Blanchard, {Maxime G} and Michela Traglia and Sarah Harris and Sheila Ulivi and Rico Rueedi and David Lamparter and Aurelien Mace and Cinzia Sala and Stefania Lenarduzzi and Belen Ponte and Menno Pruijm and Daniel Ackermann and Georg Ehret and Daniela Baptista and Ozren Polasek and Igor Rudan and Hurd, {Toby W.} and Hastie, {Nicholas D.} and Veronique Vitart and Gerard Waeber and Zolt{\'a}n Kutalik and S. Bergmann and Rosa Vargas-Poussou and Martin Konrad and Paolo Gasparini and Ian Deary and John Starr and Daniela Toniolo and P. Vollenweider and Hoenderop, {Joost G J} and Bindels, {Rene J M} and Murielle Bochud and Olivier Devuyst",

year = "2018",

month = jan,

doi = "10.1681/ASN.2017030267",

language = "English",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

publisher = "American Society of Nephrology",

}

Corre, T, Arjona, FJ, Hayward, C, Youhanna, S, de Baaij, J, Belge, H, Nagele, N, Debaix, H, Blanchard, MG, Traglia, M, Harris, S, Ulivi, S, Rueedi, R, Lamparter, D, Mace, 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, I, Starr, J, Toniolo, D, Vollenweider, P, Hoenderop, JGJ, Bindels, RJM, Bochud, M & Devuyst, O 2018, 'Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes', Journal of the American Society of Nephrology. https://doi.org/10.1681/ASN.2017030267

TY - JOUR

T1 - Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes

AU - Corre, Tanguy

AU - Arjona, Francisco J

AU - Hayward, Caroline

AU - Youhanna, Sonia

AU - de Baaij, Jeroen

AU - Belge, Hendrica

AU - Nagele, Nadine

AU - Debaix, Huguette

AU - Blanchard, Maxime G

AU - Traglia, Michela

AU - Harris, Sarah

AU - Ulivi, Sheila

AU - Rueedi, Rico

AU - Lamparter, David

AU - Mace, Aurelien

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, Gerard

AU - Kutalik, Zoltán

AU - Bergmann, S.

AU - Vargas-Poussou, Rosa

AU - Konrad, Martin

AU - Gasparini, Paolo

AU - Deary, Ian

AU - Starr, John

AU - Toniolo, Daniela

AU - Vollenweider, P.

AU - Hoenderop, Joost G J

AU - Bindels, Rene J M

AU - Bochud, Murielle

AU - Devuyst, Olivier

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=4.4×10−13) 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.

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.

U2 - 10.1681/ASN.2017030267

DO - 10.1681/ASN.2017030267

M3 - Article

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

ER -

Genome-wide Meta-analysis Unravels Novel Interactions between Magnesium Homeostasis and Metabolic Phenotypes

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Projects

HGU Core Award Apr 12 - MAr 18

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Caroline Hayward

Toby Hurd

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