Zhang Huiping, Kranzler Henry R, Weiss Roger D, Luo Xingguang, Brady Kathleen T, Anton Raymond F, Farrer Lindsay A, Gelernter Joel
Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Biol Psychiatry. 2009 Jul 15;66(2):128-36. doi: 10.1016/j.biopsych.2008.12.021. Epub 2009 Feb 12.
Opioidergic neurotransmission is critical in many, possibly all, forms of substance dependence. Several opioid-system genes have been shown to be associated with substance dependence disorders. The pro-opiomelanocortin gene (POMC) encodes several peptides important for endogenous opioidergic neurotransmission. We tested whether POMC genetic variation affects risk for substance dependence.
Five single nucleotide polymorphisms spanning POMC were examined in independent family and case-control samples. Family-based studies included 854 subjects from 319 African American (AA) families and 761 subjects from 313 European American (EA) families. Each family had a pair of siblings affected with cocaine and/or opioid dependence. Case-control studies included 791 cases (455 AAs and 336 EAs) affected with alcohol, cocaine, and/or opioid dependence and 682 control subjects (199 AAs and 483 EAs).
Family-based analyses revealed an association of rs6719226 with opioid dependence in AA families and rs6713532 with cocaine dependence in EA families (p = .010-.044). Case-control analyses demonstrated an association of rs6713532 with alcohol or cocaine dependence in EAs (p(allele-wise) = .003-.008). Moreover, the minor allele of rs1866146 was found to be a risk factor for cocaine or opioid dependence in AAs (p(allele-wise) = .010-.017) and for alcohol, cocaine, or opioid dependence in EAs (p(allele-wise) = .001-.003). Logistic regression analyses in which sex and age were considered and population stratification analyses confirmed these findings. Additionally, specific haplotypes increased risk for cocaine dependence (p = .023) in AAs and opioid dependence (p = .012) in EAs.
Given these replicated results, we conclude that variation in POMC confers vulnerability to multiple forms of substance dependence.
阿片类神经传递在许多（可能是所有）形式的物质依赖中都至关重要。已有数种阿片系统基因被证明与物质依赖障碍相关。阿片促黑皮质素原基因（POMC）编码对内源性阿片类神经传递重要的几种肽。我们测试了POMC基因变异是否影响物质依赖风险。
在独立的家系和病例对照样本中检测了跨越POMC的5个单核苷酸多态性。基于家系的研究包括来自319个非裔美国人（AA）家庭的854名受试者和来自313个欧裔美国人（EA）家庭的761名受试者。每个家庭有一对受可卡因和/或阿片类物质依赖影响的兄弟姐妹。病例对照研究包括791例受酒精、可卡因和/或阿片类物质依赖影响的病例（455名AA和336名EA）以及682名对照受试者（199名AA和483名EA）。
基于家系的分析显示，rs6719226与AA家庭中的阿片类物质依赖相关，rs6713532与EA家庭中的可卡因依赖相关（p = 0.010 - 0.044）。病例对照分析表明，rs6713532与EA中的酒精或可卡因依赖相关（p（等位基因水平）= 0.003 - 0.008）。此外，发现rs1866146的次要等位基因是AA中可卡因或阿片类物质依赖的危险因素（p（等位基因水平）= 0.010 - 0.017）以及EA中酒精、可卡因或阿片类物质依赖的危险因素（p（等位基因水平）= 0.001 - 0.003）。考虑了性别和年龄的逻辑回归分析以及人群分层分析证实了这些发现。此外，特定单倍型增加了AA中可卡因依赖的风险（p = 0.023）以及EA中阿片类物质依赖的风险（p = 0.012）。
鉴于这些重复结果，我们得出结论，POMC的变异使个体易患多种形式的物质依赖。
