A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index
A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index
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DOI：
10.1038/sj.mp.4001856
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发表时间：
2006-09-01
影响因子：
11
通讯作者：
Goldman, D.
中科院分区：
文献类型：
--
作者：
Ducci, F.;Newman, T. K.;Goldman, D.
大脑单胺能活性的变化是遗传的，并调节酗酒和其他成瘾的风险，以及食物摄入和能量消耗。单胺氧化酶A使单胺类神经递质血清素、多巴胺（DA）和去甲肾上腺素脱胺。单胺氧化酶A （MAOA）基因（Xp11.5）在其启动子区域（MAOA- lpr）中含有长度多态性，这可能会影响转录效率。我们的目标是测试(1)maaa - lpr是否有助于单胺活性的个体间变化，使用脑脊液（CSF）单胺代谢物水平进行评估；(2) maaa - lpr基因型是否影响酒精中毒和/或体重指数（BMI）。男性、无血缘关系的酗酒者（N = 278）和对照（N = 227）来自芬兰同质源人群。208名受试者的脑脊液浓度为5-羟基吲哚乙酸（5-HIAA）、纯香草酸（HVA）和3-甲氧基-4-羟基苯基乙二醇（MHPG）。根据推测的MAOA等位基因对转录活性的影响，将单等位基因和半合子基因型进行分组。MAOA-LPR基因型对脑脊液HVA浓度有显著影响（P = 0.01），但只解释了总方差的3%。基因型对5-HIAA有可检测但不显著的影响，对MHPG无影响。具体来说，在酗酒者和对照组中，赋予高MAOA活性的基因型与较低的HVA水平相关，这一发现在考虑了酗酒、BMI、身高和吸烟的潜在混杂因素后仍然存在。MAOA-LPR基因型预测BMI (P < 0.005)，高活性基因型与较低BMI相关。在本数据集中，maaa - lpr基因型与酒精中毒或相关精神表型无关。我们的研究结果表明，MAOA-LPR等位基因变异可以调节中枢神经系统的DA转换，但与我们之前的预期相反，即赋予高活性的等位基因可以预测脑脊液中较高的HVA水平。我们的结果与新兴文献一致，表明MAOA表达变化如何改变单胺能功能的复杂性更大。最后，我们的研究表明MAOA可能参与了BMI的调节。需要独立的样本来证实这一初步发现。
Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenalin. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/ or body mass index (BMI). Male, unrelated criminal alcoholics (N = 278) and controls (N = 227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P = 0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P < 0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.