title: A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism.
abstract: 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.
authors.affiliation: The Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.|The Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia.
authors.forename: F Z
authors.initials: FZ
authors.lastname: Marques
authors.affiliation: The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Eikelis
authors.affiliation: The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: R G
authors.initials: RG
authors.lastname: Bayles
authors.affiliation: The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.|The Department of Physiology, Monash University, Melbourne, VIC, Australia.
authors.forename: E A
authors.initials: EA
authors.lastname: Lambert
authors.affiliation: The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: N E
authors.initials: NE
authors.lastname: Straznicky
authors.affiliation: Neurovascular Hypertension & Kidney Disease Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.|Dobney Hypertension Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Hering
authors.affiliation: The Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia.|The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Esler
authors.affiliation: Neuropharmacology Laboratories, Baker IDI Heart and Diabetes Research Institute, Melbourne, VIC, Australia.|The Department of Pharmacology, Monash University, Melbourne, VIC, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: Head
authors.affiliation: The Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia.|The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Barton
authors.affiliation: The Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia.|Neurovascular Hypertension & Kidney Disease Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.|Dobney Hypertension Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
authors.forename: M P
authors.initials: MP
authors.lastname: Schlaich
authors.affiliation: The Central Clinical School, Faculty of Medicine, Monash University, Melbourne, VIC, Australia.|The Human Neurotransmitters Laboratories, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors.forename: G W
authors.initials: GW
authors.lastname: Lambert
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000483:Alleles; D001665:Binding Sites; D002318:Cardiovascular Diseases; D015331:Cohort Studies; D019295:Computational Biology; D003865:Major Depressive Disorder / Q000235:genetics; D000075222:Essential Hypertension; D005260:Female; D006339:Heart Rate; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D016584:Panic Disorder / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054972:Postural Orthostatic Tachycardia Syndrome / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D009638:Norepinephrine