title: hVMAT2: A Target of Individualized Medication for Parkinson's Disease.
abstract: Vesicular monoamine transporter 2 (VMAT2) is responsible for sequestering cytosolically toxic dopamine into intracellular secretory vesicles. Animal genetic studies have suggested that reduced VMAT2 activity contributes to the genetic etiology of Parkinson's disease (PD), but this role has not been established in humans. Based on human genetic association and meta-analysis, we first confirm the human VMAT2 (hVMAT2 or SLC18A2) promoter as a risk factor for PD in both family and unrelated US white people: marker rs363324 at -11.5 kb in the hVMAT2 promoter is reproducibly associated with PD in a cohort of nuclear families (p = 0.04506 in early-onset PD) and 3 unrelated US white people (meta-analysis p = 0.01879). In SH-SY5Y cells, low activity-associated hVMAT2 promoter confers high methylpiperidinopyrazole iodide cytotoxicity, which is likely attributed to functional polymorphisms bound by nuclear proteins. Interestingly, treatments with the dopamine neuron-protecting agent puerarin upregulates the promoter activity in a haplotype- and cell line-dependent manner. These pharmacogenetic findings suggest that hVMAT2 could be a risk factor and imply it as a target of genetic medications for PD.
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Xiong
authors.affiliation: School of Life Sciences, Beijing Institute of Technology, 100081, Beijing, China.|Laboratory of Psychiatric Neurogenomics, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, 02478, USA.
authors.forename: Nuomin
authors.initials: N
authors.lastname: Li
authors.affiliation: Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
authors.forename: Eden
authors.initials: E
authors.lastname: Martin
authors.affiliation: Laboratory of Psychiatric Neurogenomics, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, 02478, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Laboratory of Psychiatric Neurogenomics, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, 02478, USA.|Tianjin Mental Health Center, Tianjin Anding Hospital, 300222, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Bio-Organic and Nutritional Products Laboratory, McLean Hospital, Belmont, MA, 02478, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Bio-Organic and Nutritional Products Laboratory, McLean Hospital, Belmont, MA, 02478, USA.
authors.forename: David Yue-Wei
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Neuroregeneration Laboratories, McLean Hospital, Belmont, MA, 02478, USA.
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
authors.affiliation: Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Vance
authors.affiliation: School of Life Sciences, Beijing Institute of Technology, 100081, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, Hubei, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Laboratory of Psychiatric Neurogenomics, Division of Basic Neuroscience, McLean Hospital, Belmont, MA, 02478, USA. zhicheng_lin@hms.harvard.edu.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Lin
mesh_terms: D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D065842:Pars Compacta / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D014481:United States; D015854:Up-Regulation; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics*; D044465:White People
chemical_list: D007529:Isoflavones; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; C033607:puerarin
keywords: Association; Epigenetics; Haplotypic toxicity; Haplotypic upregulation; Meta-analysis; SLC18A2; Vesicular monoamine transporter 2