A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism

F. Z. Marques, N. Eikelis, R. G. Bayles, E. A. Lambert, N.E. Straznicky, D. Hering, Murray D. Esler, G.A. Head, D. A. Barton, M. P. Schlaich, G. W. Lambert

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    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. © 2017 Macmillan Publishers Limited, part of Springer Nature.

    Original languageEnglish
    Pages (from-to)134-141
    Number of pages8
    JournalMolecular Psychiatry
    Volume22
    Issue number1
    Early online date5 Apr 2016
    DOIs
    Publication statusPublished - 1 Jan 2017

    Fingerprint

    Norepinephrine Plasma Membrane Transport Proteins
    MicroRNAs
    Cardiovascular Diseases
    Postural Orthostatic Tachycardia Syndrome
    Genes
    Norepinephrine
    Panic Disorder
    Alleles
    Major Depressive Disorder
    3' Untranslated Regions
    Blood Pressure
    Single Nucleotide Polymorphism
    Neuroeffector Junction
    Computational Biology
    Luciferases
    Synaptic Transmission
    Down-Regulation
    Anxiety
    Heart Rate
    Binding Sites

    Cite this

    Marques, F. Z., Eikelis, N., Bayles, R. G., Lambert, E. A., Straznicky, N. E., Hering, D., ... Lambert, G. W. (2017). A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism. Molecular Psychiatry, 22(1), 134-141. https://doi.org/10.1038/mp.2016.40
    Marques, F. Z. ; Eikelis, N. ; Bayles, R. G. ; Lambert, E. A. ; Straznicky, N.E. ; Hering, D. ; Esler, Murray D. ; Head, G.A. ; Barton, D. A. ; Schlaich, M. P. ; Lambert, G. W. / A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism. In: Molecular Psychiatry. 2017 ; Vol. 22, No. 1. pp. 134-141.
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    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. {\circledC} 2017 Macmillan Publishers Limited, part of Springer Nature.",
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    Marques, FZ, Eikelis, N, Bayles, RG, Lambert, EA, Straznicky, NE, Hering, D, Esler, MD, Head, GA, Barton, DA, Schlaich, MP & Lambert, GW 2017, 'A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism' Molecular Psychiatry, vol. 22, no. 1, pp. 134-141. https://doi.org/10.1038/mp.2016.40

    A polymorphism in the norepinephrine transporter gene is associated with affective and cardiovascular disease through a microRNA mechanism. / Marques, F. Z.; Eikelis, N.; Bayles, R. G.; Lambert, E. A.; Straznicky, N.E.; Hering, D.; Esler, Murray D.; Head, G.A.; Barton, D. A.; Schlaich, M. P.; Lambert, G. W.

    In: Molecular Psychiatry, Vol. 22, No. 1, 01.01.2017, p. 134-141.

    Research output: Contribution to journalArticle

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    AU - Eikelis, N.

    AU - Bayles, R. G.

    AU - Lambert, E. A.

    AU - Straznicky, N.E.

    AU - Hering, D.

    AU - Esler, Murray D.

    AU - Head, G.A.

    AU - Barton, D. A.

    AU - Schlaich, M. P.

    AU - Lambert, G. W.

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    N2 - 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. © 2017 Macmillan Publishers Limited, part of Springer Nature.

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