OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach - PubMed (original) (raw)

OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach

Gabor Oroszi et al. Alcohol Clin Exp Res. 2009 Mar.

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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Conflict of interest statement

Disclosure/Conflict of Interest

Dr. Anton has reported receiving consultation fees and honoraria from Forest Laboratories and Alkermes (the maker of long-acting injectable naltrexone); consultation fees and grants from Bristol-Myers Squibb and Hythiam; Consultation fees, honoraria, and grants from Contral Pharma/Biotie Pharmaceuticals and Johnson & Johnson/OrthoMcNeil; consultation fees and grant funding from Pfizer; and, consultation fees from AstraZeneca, Axis Sheild, Cephalon, Drug Abuse Sciences, and Sanofi Aventis. In the near future he anticipates receiving consulting fees from Solvay Pharmaceuticals and a grant from Eli Lilly. Dr. O’Malley has reported receiving research support (grant support or clinical supplies) from Alkermes, DuPont, GlaxoSmithKline, Forest Laboratories, Lipha Pharmaceuticals, Ortho-McNeil, Bristol-Myers Squibb, Pfizer, Sanofi-Aventis, and Mallinckrodt and anticipates receiving a contract from Eli Lilly; serving as a consultant to Alkermes, Forest Laboratories, GlaxoSmithKline, Ortho-McNeil, Pfizer, Johnson & Johnson; receiving travel reimbursement from Alkermes; and that she is an inventor on patents held by Yale University entitled: “Smoking Cessation Treatments Using Naltrexone and Related Compounds”. Dr. Pettinati has reported receiving research support from Alkermes, AstraZeneca, Bristol-Myers Squibb, Cephalon, Forest Laboratories, Lipha-Merck-KGaA, Ortho- McNeil; and, serving as consultant/advisory board/speakers bureau for Alkermes, AstraZeneca, Cephalon, and Forest Laboratories. Dr. Swift has reported receiving grant funding from Ortho-McNeill and Pfizer, Inc.; serving as consultant/advisory board/speakers bureau to Alkermes, Inc., Cephalon, Ortho-McNeil, Pfizer, Inc., Transoral Pharmaceuticals, Forest Laboratories. Drs. Oroszi, Couper, Yuan and Goldman had nothing to disclose.

Figures

Figure 1

Figure 1

Schematic (non-scaled) structure of the human μ opioid receptor gene (OPRM1) based on the MOR-1 transcript variant (NM_000914.2). Positions of 10 SNPs genotyped and their dbSNP IDs are also shown. Nucleotide +1 is the A of the ATG translation initiation codon, the nucleotide 5’ to +1 is numbered −1.

Figure 2

Figure 2

(A) Scaled schematic structure of OPRM1 (on line version is in color). The yellow (top) bar represents the contig sequence spanning 20kb upstream and 10kb downstream of the 5’ and 3’ ends of the gene indicated by the green (lower) rectangle. The green vertical bars in the rectangle indicate exons. (B) Linkage disequilibrium (LD) plot of 10 OPRM1 SNPs based on 685 Caucasians in the COMBINE Study. The D’ value of each SNP pair is shown in the squares. The numbers in the squares are D’x 100. Empty squares indicate D’ = 1. Squares are colored bright red (dark grey) if the D’ value is high and the confidence in the value of D’ is high as well. The first and the last markers in each block are also displayed on the structure of OPRM1 to help the comparison between the two parts of the figure.

Figure 3

Figure 3

Close correspondence of haplotypes in the COMBINE Study and HapMap and haplotype grouping (on line version is in color). Alleles of markers (SNPs) genotyped in both datasets are highlighted in green (bold). The first allele and second allele in the haplotypes are depicted in blue (dark grey) and brown (light grey), respectively. The height of each haplotype is proportional to the CEU haplotype frequency in HapMap. Haplotypes with a frequency ≥ 3% are shown in both datasets. a). Block 1: The SNP (rs1799971) for Asn40Asp(A118G) is highlighted in bold italics b). Block 2.

Figure 3

Figure 3

Close correspondence of haplotypes in the COMBINE Study and HapMap and haplotype grouping (on line version is in color). Alleles of markers (SNPs) genotyped in both datasets are highlighted in green (bold). The first allele and second allele in the haplotypes are depicted in blue (dark grey) and brown (light grey), respectively. The height of each haplotype is proportional to the CEU haplotype frequency in HapMap. Haplotypes with a frequency ≥ 3% are shown in both datasets. a). Block 1: The SNP (rs1799971) for Asn40Asp(A118G) is highlighted in bold italics b). Block 2.

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