Crowley James J, Oslin David W, Patkar Ashwin A, Gottheil Edward, DeMaria Peter A, O'Brien Charles P, Berrettini Wade H, Grice Dorothy E
Department of Pharmacology, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
Psychiatr Genet. 2003 Sep;13(3):169-73. doi: 10.1097/00041444-200309000-00006.
Twin, family and adoption studies have suggested that vulnerability to opioid dependence may be a partially inherited trait (Cadoret et al., 1986; Merikangas et al., 1998; Tsuang et al., 1998, 2001). Studies using animal models also support a role for genetic factors in opioid dependence, and point to a locus of major effect on mouse chromosome 10 (Berrettini et al., 1994; Alexander et al., 1996), which harbors the mu opioid receptor gene (Mor1) (Kozak et al., 1994). The gene encoding the human mu opioid receptor (OPRM1) is thus an obvious candidate gene for contributing to opioid dependence. A recent report (Hoehe et al., 2000) found a significant association between a specific combination of OPRM1 single nucleotide polymorphisms (SNPs) and substance dependence.
In the current study, we genotyped 213 subjects with severe opioid dependence (89 African-Americans, 124 European-Americans) and 196 carefully screened "supercontrol" subjects (96 African-Americans, 100 European-Americans) at five SNPs residing in the OPRM1 gene. The polymorphisms include three in the promoter region (T-1793A, -1699T insertion and A-1320G) and two in exon 1 (C+17T [Ala6Val] and A+118G [Asp40Asn]).
Statistical analysis of the allele frequency differences between opioid-dependent and control subjects for each of the polymorphisms studied yielded P values in the range of 0.444-1.000. Haplotype analysis failed to identify any specific combination of SNPs associated with the phenotype.
Despite reasonable statistical power we found no evidence of association between the five mu opioid receptor polymorphisms studied and severe opioid dependence in our sample. There were, however, significant allele frequency differences between African-Americans and European-Americans for all five polymorphisms, irrespective of drug-dependent status. Linkage disequilibrium analysis of the African-American genotypes indicated linkage disequilibrium (P<0.0001) across the five-polymorphism, 1911 base pair region. In addition, only four haplotypes of these five polymorphisms are predicted to exist in African-Americans.
双胞胎、家族和收养研究表明，对阿片类药物依赖的易感性可能是一种部分可遗传的性状（卡多雷特等人，1986年；梅里坎加斯等人，1998年；苏恩等人，1998年、2001年）。使用动物模型的研究也支持遗传因素在阿片类药物依赖中起作用，并指出对小鼠10号染色体有主要影响的一个基因座（贝雷蒂尼等人，1994年；亚历山大等人，1996年），该基因座包含μ阿片受体基因（Mor1）（科扎克等人，1994年）。因此，编码人类μ阿片受体（OPRM1）的基因是导致阿片类药物依赖的一个明显的候选基因。最近的一份报告（赫厄等人，2000年）发现OPRM1单核苷酸多态性（SNP）的一种特定组合与物质依赖之间存在显著关联。
在本研究中，我们对213名患有严重阿片类药物依赖的受试者（89名非裔美国人、124名欧裔美国人）和196名经过仔细筛选的“超级对照”受试者（96名非裔美国人、100名欧裔美国人）的OPRM1基因中的五个SNP进行了基因分型。这些多态性包括启动子区域的三个（T - 1793A、 - 1699T插入和A - 1320G）和外显子1中的两个（C + 17T [Ala6Val]和A + 118G [Asp40Asn]）。
对所研究的每个多态性的阿片类药物依赖受试者和对照受试者之间的等位基因频率差异进行统计分析，得到的P值范围为0.444 - 1.000。单倍型分析未能识别出与该表型相关的任何特定SNP组合。
尽管有合理的统计效能，但我们在样本中未发现所研究的五个μ阿片受体多态性与严重阿片类药物依赖之间存在关联的证据。然而，无论药物依赖状态如何，所有五个多态性在非裔美国人和欧裔美国人之间都存在显著的等位基因频率差异。对非裔美国人基因型的连锁不平衡分析表明，在这五个多态性的1911个碱基对区域存在连锁不平衡（P < 0.0001）。此外，预计这五个多态性在非裔美国人中仅存在四种单倍型。
