Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden

Bart, Gavin; Heilig, Markus; LaForge, K. Steven; Pollak, Lotta; Leal, Suzanne M.; Ott, Jürg; Kreek, Mary Jeanne

doi:10.1038/sj.mp.4001504

Cited by 154 publications

(121 citation statements)

References 10 publications

(3 reference statements)

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“…Various investigations have evaluated the OPRM1 polymorphism in regard to drug abuse vulnerability (7,(10)(11)(12)(18)(19)(20). As compared with other studies, our results revealed a more profound (Ϸ90%) association between heroin use and the A͞G genotype.…”

Section: Discussionsupporting

confidence: 53%

“…This could be due to the rather homogenous, although small, racial and ethnic population genotyped. Bart et al (10) also found a high frequency (65%) of the 118G allele in Swedish heroin abusers from a relatively homogenous population. The higher frequency of the 118G allele in the Swedish heroin population could also reflect susceptibility to heroin ''overdose,'' thus the relationship between the 118G SNP and opioid function in respiratory brain regions is currently being explored.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

Drakenberg¹,

Nikoshkov²,

Horváth

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

104

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Opioid receptors are critical for heroin dependence, and A118G SNP of the opioid receptor gene (OPRM1) has been linked with heroin abuse. In our population of European Caucasians (n ‫؍‬ 118), Ϸ90% of 118G allelic carriers were heroin users. Postmortem brain analyses showed the OPRM1 genotype associated with transcription, translation, and processing of the human striatal opioid neuropeptide system. Whereas down-regulation of preproenkephalin and preprodynorphin genes was evident in all heroin users, the effects were exaggerated in 118G subjects and were most prominent for preproenkephalin in the nucleus accumbens shell. Reduced opioid neuropeptide transcription was accompanied by increased dynorphin and enkephalin peptide concentrations exclusively in 118G heroin subjects, suggesting that the peptide processing is associated with the OPRM1 genotype. Abnormal gene expression related to peptide convertase and ubiquitin͞proteosome regulation was also evident in heroin users. Taken together, alterations in opioid neuropeptide systems might underlie enhanced opiate abuse vulnerability apparent in 118G individuals.drug abuse ͉ dynorphin ͉ enkephalin ͉ mRNA

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 97%

μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

Drakenberg¹,

Nikoshkov²,

Horváth

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

104

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“…PCR products were electrophoresed on agarose gel to verify amplification size and were then purified and sequenced at The Rockefeller University. The amplification and sequencing primers have been described previously (Bart et al, 2004) and we have compared the accuracy of these primers with a TaqMan-based methodology and found the concordance of genotyping results between the two methods to be greater than 99% (Proudnikov et al, 2004). Electropherograms were analyzed by two independent readers who were blind to the neuroendocrine data.…”

Section: Genotypingmentioning

confidence: 99%

“…Self-administration of opioids, cocaine, alcohol, and nicotine does not develop or is reduced in mu opioid receptor gene (OPRM1) knockout mice (Becker et al, 2000;Berrendero et al, 2002;Hall et al, 2001;Mathon et al, 2005;Roberts et al, 2000). We have shown that a functional single nucleotide polymorphism in the first exon of OPRM1 accounts for up to 21% of the attributable risk for developing heroin addiction and 11% of the risk for developing alcoholism in cohorts from central Sweden (Bart et al, 2004(Bart et al, , 2005. This A118G polymorphism (rs1799971) results in an asparagine to aspartic acid substitution at amino-acid position 40 and leads to increased receptor-binding affinity for the endogenous opioid beta-endorphin and increased potency of ion channel activation following beta-endorphin binding (Bond et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

Bart

LaForge

Borg

et al. 2006

Neuropsychopharmacol

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The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic-pituitary-adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.

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“…A number of studies have reported positive association between OPRM1 functional variant A118G and OD, [27][28][29][30] cocaine dependence (CD) 31 or AD. [31][32][33][34] Moreover, three studies adopting haplotype-based approaches also demonstrated the association between OPRM1 variants and DD or AD.…”

Section: Introductionmentioning

confidence: 99%

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

et al. 2007

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Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P < 0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (v 2 = 14.82, degrees of freedom (d.f.) = 1, P < 0.001), CD (v 2 = 9.19, d.f. = 1, P = 0.002) and OD (v 2 = 20.68, d.f. = 1, P < 0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P = 0.03, b = 1.86, odds ratio (OR) = 6.43) and especially on OD (P < 0.001, b = 3.92, OR = 50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (v 2 = 8.12, d.f. = 1, P = 0.004). Logistic regression analyses also revealed its risk effect on AD (P = 0.009, b = 1.06, OR = 2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.

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Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden

Cited by 154 publications

References 10 publications

μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

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