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defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (<jats:italic>SLC6A2<\/jats:italic>) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of <jats:italic>SLC6A2<\/jats:italic> was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAF<jats:sub>cases<\/jats:sub>\u2009=\u20090.431, MAF<jats:sub>controls<\/jats:sub>\u2009=\u20090.368) upstream of <jats:italic>MIR579<\/jats:italic> was associated with panic disorder in patients (<jats:italic>p<\/jats:italic><jats:sub>allelic<\/jats:sub>\u2009=\u20090.004, <jats:italic>n<\/jats:italic><jats:sub>cases<\/jats:sub>\u2009=\u2009506, <jats:italic>n<\/jats:italic><jats:sub>controls<\/jats:sub>\u2009=\u2009506) and with higher trait anxiety in healthy individuals (<jats:italic>p<\/jats:italic><jats:sub>ASI<\/jats:sub>\u2009=\u20090.029, <jats:italic>p<\/jats:italic><jats:sub>ACQ<\/jats:sub>\u2009=\u20090.047, <jats:italic>n<\/jats:italic>\u2009=\u20093112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective <jats:italic>MIR579<\/jats:italic> expression and <jats:italic>SLC6A2<\/jats:italic> repression in vivo (<jats:italic>p<\/jats:italic>\u2009=\u20090.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (<jats:italic>F<\/jats:italic>(2, 270)\u2009=\u20095.47, <jats:italic>p<\/jats:italic>\u2009=\u20090.005). Fine-tuning of noradrenaline homeostasis by a <jats:italic>MIR579<\/jats:italic> genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.<\/jats:p>","DOI":"10.1038\/s41398-018-0278-4","type":"journal-article","created":{"date-parts":[[2018,10,19]],"date-time":"2018-10-19T16:54:14Z","timestamp":1539968054000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety"],"prefix":"10.1038","volume":"8","author":[{"given":"L. 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H.-U.W. has been a member of advisory boards of several pharmaceutical companies. He received travel reimbursements and research grant support from Essex Pharma, Sanofi, Pfizer, Organon, Servier, Novartis, Lundbeck, and Glaxo Smith Kline. V.A. is a member of advisory boards and\/or gave presentations for the following companies: Astra-Zeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer, and Wyeth. He also received research grants from Astra-Zeneca, Lundbeck, and Servier. He chaired the committee for the \u201cWyeth Research Award Depression and Anxiety\u201d. A.S. received research from Lundbeck and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co, Lundbeck, Pfizer, Wyeth, and UCB. Educational grants were given by the Boehringer Ingelheim Fonds and the Eli Lilly International Foundation. A.R. has received a research grant from Medice and speaker\u2019s honoraria from Medice and neuraxpharm. The other authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"226"}}