In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 1 ( 2018-1), p. 335-348
Abstract:
Magnesium (Mg 2+ ) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg 2+ , which is crucial for Mg 2+ 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 Mg 2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 ( P= 4.4×10 −13 ) near TRPM6 , which encodes an epithelial Mg 2+ 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 Mg 2+ regulated the expression of the highly conserved ARL15 ortholog arl15b , and arl15b knockdown resulted in renal Mg 2+ 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 Mg 2+ deficiency to insulin resistance and obesity.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2017030267
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
2029124-3
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