SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism

Zhicheng Lin, Donna Walther, Xiao Ying Yu, Suxia Li, Tomas Drgon, George R. Uhl

Research output: Contribution to journalArticle

Abstract

The vesicular monoamine transporter 2 (VMAT2, SLC18A2) takes up cytosolic monoamines into intracellular secretory vesicles, preventing their neurotoxicity in the cytosol and discharging them into extracellular space by exocytosis. It has been shown that one-copy deletion of the VMAT2 gene increases locomotion activity significantly in response to drug treatments and dopamine neuron death rate in response to neurotoxin treatments in knockout mice. Little is known about promoter polymorphisms and their influence on SLC18A2 promoter activity. We have re-sequenced a 17.4 kb DNA in the SLC18A2 promoter region for Caucasians and revealed 47 polymorphisms that confer 13 haplotypes. One of the haplotypes reaches a frequency as high as 65%, likely due to positive selection. In vitro analysis showed a 20% difference in promoter activity between two frequent haplotypes and identified some of the polymorphisms that influence promoter activity. Four haplotype-defining single nucleotide polymorphisms (hdSNPs) can define the frequent haplotypes and by genotyping these hdSNPs, we find that haplotypes with -14234G and -2504C of SLC18A2 promoter region represent a protective factor against alcoholism (P = 0.0038 by Fisher's exact tests). Therefore, SLC18A2 promoter haplotypes defined here create a foundation for transcriptional characterization of individuality and for association study on monoamine-related human diseases.

Original languageEnglish (US)
Pages (from-to)1393-1404
Number of pages12
JournalHuman Molecular Genetics
Volume14
Issue number10
DOIs
StatePublished - May 15 2005
Externally publishedYes

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Haplotypes
Alcoholism
Genetic Promoter Regions
Single Nucleotide Polymorphism
Vesicular Monoamine Transport Proteins
Protective Factors
Dopaminergic Neurons
Exocytosis
Gene Deletion
Secretory Vesicles
Neurotoxins
Extracellular Space
Locomotion
Knockout Mice
Individuality
Cytosol
Mortality
DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics

Cite this

SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism. / Lin, Zhicheng; Walther, Donna; Yu, Xiao Ying; Li, Suxia; Drgon, Tomas; Uhl, George R.

In: Human Molecular Genetics, Vol. 14, No. 10, 15.05.2005, p. 1393-1404.

Research output: Contribution to journalArticle

Lin, Zhicheng ; Walther, Donna ; Yu, Xiao Ying ; Li, Suxia ; Drgon, Tomas ; Uhl, George R. / SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 10. pp. 1393-1404.
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