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OPRM1 Asn40Asp Predicts Response to Naltrexone Treatment: A Haplotype-Based Approach

Authors

  • Gabor Oroszi,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • Raymond F. Anton,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • Stephanie O’Malley,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • Robert Swift,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • Helen Pettinati,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • David Couper,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • Qiaoping Yuan,

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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  • David Goldman

    1. From the Center for Drug and Alcohol Programs, Medical University of South Carolina (GO, RFA), Charleston, South Carolina; Substance Abuse Treatment Unit, Yale University School of Medicine (SM), New Haven, Connecticut; Roger Williams Medical Center and Providence VA Medical Center, Brown University (RS), Providence, Rhode Island; Treatment Research Center, University of Pennsylvania School of Medicine (HP), Philadelphia, Pennsylvania; Collaborative Studies Coordinating Center, University of North Carolina (DC), Chapel Hill, North Carolina; and Laboratory of Neurogenetics (QY, DG), NIAAA, NIH, Rockville, Maryland.
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Reprint requests: Raymond F. Anton, MD, Center for Drug and Alcohol Programs, Medical University of South Carolina, 67 President St., PO Box 250861, Charleston, SC 29425; Fax: 843-792-17241; E-mail: antonr@musc.edu

Abstract

Background:  Individualized pharmacotherapy requires identification of genetic variants predictive of treatment response. In OPRM1, Asn40Asp has been reported to be predictive of response to naltrexone treatment. Nevertheless, the in vitro function of the polymorphism remains elusive and over 300 OPRM1 sequence variants have been identified to date. Therefore we used a haplotype-based approach to capture information of other genetic variants that might predict treatment response to naltrexone in the COMBINE Study.

Methods:  5′ nuclease genotyping assays (TaqMan®) were applied for 10 SNPs. Five-locus haplotypes in 2 OPRM1 haplotype blocks were assigned to Caucasian participants. The relationship of the haplotypes to medication reflected by “good clinical outcome” was analyzed in 306 Caucasians treated without Combined Behavioral Intervention and with either naltrexone or placebo.

Results:  A significant haplotype by medication interaction (p = 0.03) was found in OPRM1 block 1. Naltrexone-treated alcoholics with haplotype AGCCC, the single haplotype carrying the Asp40 allele had the highest percent of good clinical outcome. When interaction of genotypes at each of the 5 loci comprising block 1 with medication was examined, only the Asn40/Asp40 and Asp40/Asp40 genotypes were found to significantly interact with naltrexone treatment. No haplotype by medication interaction was documented in OPRM1 block 2.

Conclusions:  Our haplotype-based approach confirms that the single OPRM1 locus predictive of response to naltrexone treatment is Asn40Asp in exon 1. A substantial contribution of any other OPRM1 genetic variant to interindividual variations in response to naltrexone treatment (at least in terms of good clinical outcome) is not supported by our findings.

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