Need A C, Ahmadi K R, Spector T D, Goldstein D B
Department of Biology, University College London, The Darwin Building, Gower Street, London WC1E 6BT.
Ann Hum Genet. 2006 May;70(Pt 3):293-303. doi: 10.1111/j.1529-8817.2005.00228.x.
Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI > or = 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals (MAOA:chi2= 15.45, p = 0.004; MAOB:chi2= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the 'at risk genotype'--low activity genotypes at both the MAOA and MAOB loci--shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets.
人类和动物研究表明多巴胺与食欲调节有关，家族研究显示体重指数（BMI）有很强的遗传成分。多巴胺的可用性主要由三种酶（儿茶酚-O-甲基转移酶（COMT）、单胺氧化酶A（MAOA）和单胺氧化酶B（MAOB））以及多巴胺转运体SLC6A3控制，并且每个基因都有一个特征明确的功能变体。在此，我们综合研究这四种功能多态性，以调查多巴胺水平的遗传变异如何影响一个包含1150人的队列中的肥胖风险，其中240人被定义为肥胖（BMI≥30）。COMT和SLC6A3多态性与体重、BMI或肥胖风险均无关联。然而，我们发现，肥胖个体中MAOA和MAOB的低活性基因型均过量（MAOA：卡方=15.45，p = 0.004；MAOB：卡方=8.05，p = 0.018）。此外，MAOA基因型与体重（p = 0.0005）和BMI（p = 0.001）均显著相关。综合考虑，“风险基因型”——MAOA和MAOB位点的低活性基因型——显示肥胖的相对风险为5.01。这些结果尚未得到重复验证，鉴于复杂性状遗传学的经验，在解释时需谨慎。然而，该研究表明MAOA和MOAB变体均有影响，首次提示多巴胺可用性（而非MAOA的其他作用）与人的肥胖有关。因此，评估复制数据集中的关联是当务之急。
