Aklillu Eleni, Karlsson Sara, Zachrisson Olof O, Ozdemir Vural, Agren Hans
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
Pharmacogenet Genomics. 2009 Apr;19(4):267-75. doi: 10.1097/FPC.0b013e328328d4d3.
Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy.
In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF.
AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD.
The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.
单胺氧化酶 -A（MAO -A）是一种关键的线粒体酶，可代谢生物胺神经递质，如多巴胺和血清素。非典型抑郁症（AD）患者对单胺氧化酶抑制剂（MAOIs）治疗尤为敏感。生物标志物检测对于AD的快速诊断以及识别那些脑内神经递质代谢改变且可能对MAOI治疗有选择性反应的患者至关重要。
在118例对MAOI治疗无经验的斯堪的纳维亚难治性抑郁症患者样本中，我们研究了常见的MAOA功能性启动子多态性（MAOA -uVNTR）、脑脊液（CSF）神经递质代谢物与AD易感性之间的关联。在脑脊液中测量了多巴胺（高香草酸，HVA）、血清素（5 - 羟吲哚乙酸）和去甲肾上腺素（3 - 甲氧基 - 4 - 羟基苯乙二醇）的代谢物。
AD与女性性别以及脑脊液中较高的HVA相关（P = 0.008）。MAOA -uVNTR短等位基因携带者在患有AD的女性中显著过多（P = 0.005；优势比 = 4.76；95%置信区间 = 1.5 - 13.1；统计效能 = 80.0%）。此外，MAOA -uVNTR基因型显著影响女性脑脊液中HVA浓度（P = 0.01），并且与5 - 羟吲哚乙酸浓度呈现出强烈趋势相关（P = 0.057）。中介统计分析表明脑脊液HVA浓度是MAOA -uVNTR基因型与AD之间关系的关键驱动因素。
MAOA -uVNTR与AD易感性和多巴胺代谢物（HVA）浓度的关联，进一步从生物学角度支持了高MAO -A酶活性作为通过改变多巴胺周转导致AD遗传易感性的机制因素。我们的观察结果为MAOA -uVNTR短等位基因作为高活性变体的体内功能意义提供了新证据。
