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Human Molecular Genetics Advance Access published online on April 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi148
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Published by Oxford University Press 2005
Received February 7, 2005
Revised April 4, 2005
Accepted April 4, 2005

Article

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

Zhicheng Lin 1*, Donna Walther 2, Xiao-Ying Yu 2, Suxia Li 2, Tomas Drgon 2, and George R. Uhl 2

1 Molecular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, U. S. A.
2 Molecular Neurobiology Branch, IRP, NIDA, NIH, DHHS, Baltimore, Maryland 21224, U. S. A.

* To whom correspondence should be addressed.
Zhicheng Lin, E-mail: zlin{at}intra.nida.nih.gov


  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 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 the 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.


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