NDLI: A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain

Content Provider	PubMed Central
Author	Yuferov, Vadim Ji, Fei Nielsen, David A. Orna, Levran Ho, Ann Susan, Morgello Shi, Ruijin Ott, Jurg Kreek, Mary Jeanne
Abstract	Dynorphin peptides and the kappa opioid receptor play important roles in the rewarding properties of cocaine, heroin and alcohol. We tested polymorphisms of the prodynorphin gene (PDYN) for association with cocaine dependence and cocaine/alcohol codependence. We genotyped six SNPs, located in the promoter region, exon 4 coding and 3′ untranslated region (UTR), in 106 Caucasians and 204 African Americans who were cocaine dependent, cocaine/alcohol codependent or controls. In Caucasians, we found point-wise significant associations of 3′UTR SNPs (rs910080, rs910079, and rs2235749) with cocaine dependence and cocaine/alcohol codependence. These SNPs are in high linkage disequilibrium, comprising a haplotype block. The haplotype CCT was significantly experiment-wise associated with cocaine dependence and with combined cocaine dependence and cocaine/alcohol codependence (FDR, q=0.04 and 0.03, respectively). We investigated allele-specific gene expression of PDYN, using SNP rs910079 as a reporter, in postmortem human brains from eight heterozygous subjects, using SNaPshot assay. There was significantly lower expression for C allele (rs910079), with ratios ranging from 0.48 to 0.78, indicating lower expression of the CCT haplotype of PDYN in both the caudate and nucleus accumbens. Analysis of total PDYN expression in 43 postmortem brains also showed significantly lower levels of preprodynorphin mRNA in subjects having the risk CCT haplotype. This study provides evidence that a 3′UTR PDYN haplotype, implicated in vulnerability to develop cocaine addiction and/or cocaine/alcohol codependence, is related to lower mRNA expression of the PDYN gene in human dorsal and ventral striatum.
Related Links	http://dx.doi.org/10.1038/npp.2008.187
Ending Page	1197
Page Count	13
Starting Page	1185
File Format	PDF
ISSN	0893133X
e-ISSN	1740634X
Journal	Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Issue Number	5
Volume Number	34
Language	English
Publisher Date	2009-04-01
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pharmacology Psychiatry and Mental Health

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