Norepinephrine released from sympathetic nerves is removed from the neuroeffector junction via the action of the norepinephrine transporter (NET). NET impairment is evident in several clinically important conditions including major depressive disorder (MDD), panic disorder (PD), essential hypertension and the postural orthostatic tachycardia syndrome (POTS). We aimed to determine whether a single nucleotide polymorphism (SNP) in the 3’ untranslated region (UTR) of the NET gene is associated with NET impairment and to elucidate the mechanisms involved. The analyses were carried out in two cohorts of European ancestry, which included healthy controls and MDD, PD, hypertensive and POTS patients. Compared with controls, cases had significantly higher prevalence of the T allele of rs7194256 (C/T), arterial norepinephrine, depression and anxiety scores, larger left ventricular mass index, higher systolic and diastolic blood pressures, and heart rate. Bioinformatic analysis identified that the microRNA miR-19a-3p could bind preferentially to the sequence created by the presence of the T allele. This was supported by results of luciferase assays. Compared with controls, cases had significantly lower circulating miR-19a-3p, which was associated with pathways related to blood pressure and regulation of neurotransmission. In vitro norepinephrine downregulated miR-19a-3p. In conclusion, the T allele of the rs7194256 SNP in the 3’UTR of the NET gene is more prevalent in diseases where NET impairment is evident. This might be explained by the creation of a binding site for the microRNA miR-19a-3p. A defect in NET function may potentiate the sympathetic neurochemical signal, predisposing individuals with affective diseases to increased risk of cardiovascular disease development.
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This work was supported by research grants from the National Health & Medical Research Council of Australia (NHMRC). The Baker IDI Heart & Diabetes Institute is supported in part by the Victorian Government's OIS Program. FZM is supported by NHMRC (APP1052659) and National Heart Foundation (PF12M6785) co-shared Early Career Fellowships. GWL, MDE, GAH and MPS are supported by National Health and Medical Research Council of Australia (NHMRC) fellowships.
The laboratories of Professors Lambert, Esler and Schlaich currently or recently received research funding from Medtronic, Abbott Pharmaceuticals, Servier Australia and Allergan. Professor Lambert has acted as a consultant for Medtronic and has received honoraria or travel support for presentations from Pfizer, Wyeth Pharmaceuticals, Servier and Medtronic. Professor Esler serves on scientific advisory boards of Abbott (formerly Solvay) Pharmaceuticals and Medtronic. Professor Schlaich serves on scientific advisory boards for Abbott (formerly Solvay) Pharmaceuticals, Novartis Pharmaceuticals and Medtronic, and has received honoraria and travel support from Abbott, Servier, Novartis and Medtronic.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Marques, F., Eikelis, N., Bayles, R. et al. A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism. Mol Psychiatry 22, 134–141 (2017). https://doi.org/10.1038/mp.2016.40
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