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

Corre, Tanguy;Arjona, Francisco J.;Hayward, Caroline;Youhanna, Sonia;Devuyst, Olivier;et.al.
(2017) Journal of the American Society of Nephrology — Vol. 29, n° 1, p. 335-348 (2017)

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  • Corre, Tanguy
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  • Arjona, Francisco J.
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  • Hayward, Caroline
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  • Youhanna, Sonia
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  • Devuyst, OlivierUCLouvain
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Abstract
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.
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Corre, T., Arjona, F. J., Hayward, C., Youhanna, S., de Baaij, J. H. F., Belge, H., Nägele, N., Debaix, H., Blanchard, M. G., Traglia, M., Harris, S. E., Ulivi, S., Rueedi, R., Lamparter, D., Macé, A., Sala, C., Lenarduzzi, S., Ponte, B., Pruijm, M., et al. (2017). Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes. Journal of the American Society of Nephrology, 29(1), 335-348. https://doi.org/10.1681/asn.2017030267 (Original work published 2017)