Genetic Evidence for the Association of the Hypothalamic-Pituitary-Adrenal (HPA) Axis with ADHD and Methylphenidate Treatment Response
Genetic Evidence for the Association of the Hypothalamic-Pituitary-Adrenal (HPA) Axis with ADHD and Methylphenidate Treatment Response
复制标题
DOI：
10.1007/s12017-012-8202-1
复制
发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Joober, Ridha
中科院分区：
文献类型：
--
作者：
Fortier, Marie-Eve;Sengupta, Sarojini M.;Joober, Ridha
暴露于压力源会导致一系列自主神经、内分泌和行为反应。这种应激反应的一个关键途径是下丘脑-垂体-肾上腺（HPA）轴，它导致循环皮质醇短暂增加，皮质醇通过两个相关的配体激活的转录因子发挥作用：糖皮质激素受体（GR）和盐皮质激素受体（MR）。这些受体的遗传多态性已被证明会影响HPA轴的反应性，HPA轴的慢性失调与几种精神疾病的发生有关。该研究的目的是测试NR 3C 1中的四种功能多态性（编码GR：ER 22/23 EK-rs6189、N363 S-rs6195、BclI-rs 41423247、A3669 G-rs6198）和NR 3C 2中的两种功能多态性（编码MR：215 G/C-rs 2070951、I180 V-rs 5522）与儿童ADHD之间的关联。进行基于家庭的关联测试（FBAT），对ADHD进行分类诊断，与ADHD相关的行为和认知表型，以及在一项为期2周的哌甲酯双盲安慰剂对照试验中评估的治疗反应。一个特定的单倍型（G：A：G：G; ER 22/23 EK-N363 S-BclI-A3669 G）与ADHD相关行为（特别是思维和注意力问题、攻击行为）、对立违抗性障碍共病和执行功能域显著相关。还观察到与治疗反应的相关性（通过Conners教师和受限学术状况量表评估）。与此相反，MR基因多态性与任何测试的变量无关。据我们所知，这是第一份报告显示NR 3C 1和ADHD的功能多态性之间的关联，提供了遗传证据HPA轴参与疾病和治疗反应。
Exposure to stressors results in a spectrum of autonomic, endocrine, and behavioral responses. A key pathway in this response to stress is the hypothalamic-pituitary-adrenal (HPA) axis, which results in a transient increase in circulating cortisol, which exerts its effects through the two related ligand-activated transcription factors: the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Genetic polymorphisms in these receptors have been shown to influence HPA axis reactivity, and chronic dysregulation of the HPA axis has been associated with the development of several psychiatric disorders. The objective of the study was to test the association between four functional polymorphisms in NR3C1 (encoding GR: ER22/23EK-rs6189, N363S-rs6195, BclI-rs41423247, A3669G-rs6198) and two in NR3C2 (encoding MR: 215G/C-rs2070951, I180 V-rs5522) with childhood ADHD. Family-based association tests (FBAT) were conducted with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, as well as with treatment response assessed in a 2-week, double-blind, placebo-controlled trial with methylphenidate. A specific haplotype (G:A:G:G; ER22/23EK- N363S- BclI- A3669G) of NR3C1 showed a significant association with behaviors related to ADHD (particularly thought and attention problems, aggressive behavior), comorbidity with oppositional defiant disorder, and executive function domains. An association was also observed with treatment response (assessed by the Conners'-Teachers and Restricted Academic Situation Scale). In contrast, MR gene polymorphisms were not associated with any of the variables tested. To the best of our knowledge, this is the first report showing an association between functional polymorphisms in NR3C1 and ADHD, providing genetic evidence for involvement of the HPA axis in the disorder and treatment response.