Dynorphin peptides and the
kappa-opioid receptor are important 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 single nucleotide polymorphisms (SNPs), located in the promoter region, exon 4 coding, and
3' untranslated region, 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 (false discovery rate, 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.