A genetic basis for the variable effect of smoking/nicotine on Parkinson’s disease

Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson’s disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nic...

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Bibliographic Details
Published in:	The pharmacogenomics journal Vol. 13; no. 6; pp. 530 - 537
Main Authors:	Hill-Burns, E M, Singh, N, Ganguly, P, Hamza, T H, Montimurro, J, Kay, D M, Yearout, D, Sheehan, P, Frodey, K, Mclear, J A, Feany, M B, Hanes, S D, Wolfgang, W J, Zabetian, C P, Factor, S A, Payami, H
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2013 Nature Publishing Group
Subjects:	631/208/212/1728 692/699/375/365/1718 Animals Biomedical and Life Sciences Biomedicine Cigarette smoking Clinical trials Complications and side effects Dopamine Dopamine - metabolism Drosophila Gene Expression Gene-Environment Interaction Genetic aspects Genetic variation Genome-Wide Association Study Genomes Genotypes Human Genetics Humans Insects Models, Biological Movement disorders Neurodegenerative diseases Nicotine Nicotine - adverse effects Oncology original-article Paraquat Parkinson Disease - etiology Parkinson Disease - genetics Parkinson Disease - metabolism Parkinson's disease Pharmacogenomics Pharmacotherapy Physiological aspects Psychopharmacology Risk factors Smoking Smoking - adverse effects Substantia nigra Synaptic vesicles United States nicotine Parkinson’s disease
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Summary:	Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson’s disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila . We identified SV2C , which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra ( P =1 × 10 −7 for gene–smoking interaction on PD risk), and CG14691 , which is predicted to encode a synaptic-vesicle protein in Drosophila ( P =2 × 10 −11 for nicotine–paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful ( P =5 × 10 −10 ). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	1470-269X 1473-1150 1473-1150
DOI:	10.1038/tpj.2012.38