Abstract
BackgroundVariation in response to the hedonic and adverse effects of a substance is in part an inherited factor that may influence its use, abuse and dependence. The mu opioid receptor is the primary site of action for opiates and individuals with polymorphisms in this receptor appear to have variation in the CNS effects of opiates. Several studies have suggested that this receptor may also mediate some of the effects of non-opioid drugs, such as alcohol. The purpose of this study was to investigate associations between 13 single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) with self-reported responses to alcohol, an endophenotype associated with the development of alcohol dependence, in American Indians living on eight contiguous reservations.MethodsEach participant gave a blood sample and completed a structured diagnostic interview. Additionally, response to alcohol was indexed using the expectation version of the subjective high assessment scale (SHAS-E). SNPs were genotyped in 251 participants and data analyses were conducted using SOLAR.ResultsThe estimated heritability (h2) for the SHAS-E phenotypes ranged from 0.01 to 0.28. Endorsing the expectation of a more intense response on one or more of the following items from the SHAS-E: buzzed, clumsy, dizzy, drunk, effects, high, nausea, sleepy, talkative, terrible, and/or uncomfortable after imbibing 2–3 drinks was significantly associated with having at least one minor allele for at least one of 7 SNPs (p < 0.01) in the OPRM1 receptor gene.ConclusionThese studies provide data to suggest that the minor allele, for most of the polymorphisms in the OPRM1 receptor gene investigated, was found to be associated with a more intense, and/or more adverse, response to alcohol, traits that are significantly correlated with lowered quantity of alcohol consumption and less susceptibility to dependence in this Indian population. These data further suggest that making conclusions on the role of the mu opiod receptor gene in the development of alcohol dependence may be limited if only one polymorphism in the gene is evaluated in isolation.
Highlights
Variation in response to the hedonic and adverse effects of a substance is in part an inherited factor that may influence its use, abuse and dependence
Because the allele frequencies observed in this Indian population for each of the single nucleotide polymorphism (SNP) is intermediate between the allele frequencies observed for the European (CEU) and Asian (JC) HapMap populations, we investigated the linkage disequilibrium structure in these populations
The mean age of the sample was 30.2 (± 0.7) yrs, there were 110 males and 141 females with a mean of 11.5(0.1) yrs of education, 60% of the sample was over 50% Native American heritage as estimated by their federal Indian blood quantum and 55% reported income of less than $20,000 per annum
Summary
Variation in response to the hedonic and adverse effects of a substance is in part an inherited factor that may influence its use, abuse and dependence. The mu opioid receptor is the primary site of action for opiates and individuals with polymorphisms in this receptor appear to have variation in the CNS effects of opiates. Wide inter-patient variability in response to, and in the dosage requirement for morphine have been demonstrated in cancer patients receiving morphine for pain control [3]. It appears that a number of genetic and environmental factors can lead to significant variation in the doses of a drug necessary to produce therapeutic, hedonic and/or adverse effects. The most common single nucleotide polymorphism (SNP) reported on is A118G (rs1799971), which encoded the Asp40Asn codon change with most data suggesting that it is a functional variant [4,12]
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