Corre, TanguyTanguyCorreArjona, Francisco JFrancisco JArjonaHayward, CarolineCarolineHaywardYouhanna, SoniaSoniaYouhannade Baaij, Jeroen H FJeroen H Fde BaaijBelge, HendricaHendricaBelgeNägele, NadineNadineNägeleDebaix, HuguetteHuguetteDebaixBlanchard, Maxime GMaxime GBlanchardTraglia, MichelaMichelaTragliaHarris, Sarah ESarah EHarrisUlivi, SheilaSheilaUliviRueedi, RicoRicoRueediLamparter, DavidDavidLamparterMacé, AurélienAurélienMacéSala, CinziaCinziaSalaLenarduzzi, StefaniaStefaniaLenarduzziPonte, BelenBelenPontePruijm, MennoMennoPruijmAckermann, DanielDanielAckermann0000-0003-0550-354XEhret, GeorgGeorgEhretBaptista, DanielaDanielaBaptistaPolasek, OzrenOzrenPolasekRudan, IgorIgorRudanHurd, Toby WToby WHurdHastie, Nicholas DNicholas DHastieVitart, VeroniqueVeroniqueVitartWaeber, GeràrdGeràrdWaeberKutalik, ZoltánZoltánKutalikBergmann, SvenSvenBergmannVargas-Poussou, RosaRosaVargas-PoussouKonrad, MartinMartinKonradGasparini, PaoloPaoloGaspariniDeary, Ian JIan JDearyStarr, John MJohn MStarrToniolo, DanielaDanielaTonioloVollenweider, PeterPeterVollenweiderHoenderop, Joost G JJoost G JHoenderopBindels, René J MRené J MBindelsBochud, MurielleMurielleBochudDevuyst, OlivierOlivierDevuyst2024-10-252024-10-252018-01https://boris-portal.unibe.ch/handle/20.500.12422/157260Magnesium (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.enGene-environment interaction Genetic determinants Magnesium homeostasis Metabolic syndrome Tubular transport zebrafish600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biologyarticle10.7892/boris.1096632909302810.1681/ASN.2017030267