title: Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women.
abstract: The vesicular monoamine transporter can protect against toxins that induce an acute parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease (PD) leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) which affect its quantitative expression might therefore serve as genetic risk factors for PD. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain-of-function haplotypes that display significantly increased transcriptional activity from the reference element. These gain-of-function haplotypes were tested for association with PD and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for PD.
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 10028, USA. ceg2004@med.cornell.edu
authors.forename: Charles E
authors.initials: CE
authors.lastname: Glatt
authors.forename: Angelika D
authors.initials: AD
authors.lastname: Wahner
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: White
authors.forename: Andres
authors.initials: A
authors.lastname: Ruiz-Linares
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
mesh_terms: D001741:Black or African American / Q000235:genetics; D001483:Base Sequence; D002140:California; D017931:DNA Primers; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D022142:Secretory Vesicles / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D017931:DNA Primers; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D004298:Dopamine