DAT1和DRD4基因启动子区甲基化水平与注意缺陷多动障碍发病及临床症状的关联研究

发布时间：2018-04-15 02:20

  本文选题：注意缺陷多动障碍 + 表观遗传学　； 参考：《昆明医科大学》2016年硕士论文

【摘要】：目的：探索注意缺陷多动障碍(Attention Deficit Hyperactivity Disorder, ADHD)患儿和正常儿童在多巴胺转运体基因(DAT1/SLC6A3基因)、多巴胺D 4受体基因(DRD4基因)启动子区CpG岛甲基化状态的差异,并了解DAT1、DRD4基甲基化水平与ADHD患儿临床症状严重程度的相关性,旨在从表观遗传学角度进一步了解和阐明ADHD患病的遗传学机制、以及临床症状和多巴胺神经递质系统甲基化水平之间的关系。方法：收集111例ADHD患者及118例对照组儿童的外周血及一般人口学资料,同时对11 1例ADHD患者的临床症状、认知功能、家族史进行评定。采用亚硫酸氢钠测序法,明确111例ADHD患者及118例对照儿童的DAT1基因、DRD4基因的启动子区CpG岛目标片段中每一个CpG位点的甲基化状态。结果：1、病例组和对照组在DAT1和DRD4基因启动子区总体发生甲基化的频数比例的比较中差异均无统计学意义(P0.05);DAT1基因启动子区CpG岛片段中,第17个CpG位点病例组发生甲基化的频数比例较对照组高(P0.05); DRD4基因启动子区CpG岛片段中,第8个CpG位点病例组发生甲基化的频数比例较对照组高(P0.05)；2、在所有样本中,DAT1基因启动子区发生甲基化的频数比例为男性高于女性(P0.05), DRD4基因启动子区发生甲基化频数的比例则为女性高于男性(P0.05)；病例组中DAT1基因启动子区发生甲基化的频数比例为男性高于女性(P0.05)；对照组中DRD4基因启动子区发生甲基化的频数比例为女性高于男性(P0.05)。3、在所有样本中,7岁年龄组在DAT1基因启动子区发生甲基化的频数比例高于1-7岁组(P0.05)；病例组中7岁年龄组在DAT1基因启动子区发生甲基化的频数比例亦高于1-7岁组(P0.05)；病例组中病程4年组在DAT1基因启动子区发生甲基化的频数比例高于病程为1-4年组的ADHD患者(P0.05)。4.病例组中,无抑郁、焦虑、ADHD家族史的患者其DAT1启动子区甲基化频数比例高于有相关家族史的患者(P0.05)。5.病例组中,对立违抗障碍量表(oppositional defiant disorder, ODD)9分的患儿其DAT1基因甲基化频数比例较ODD量表得分≥9分的患儿高,且DAT1基因甲基化率与ODD量表得分呈负相关(P均0.05);DAT1和DRD4基因甲基化频数比例在ADHD-RS-Ⅳ (ADHD评估量表)总分(g0分组与30分组)、注意缺陷分(≤17分组与17分组)、多动冲动分(≤13分组与13分组)以上两两组间的比较中均未检出统计学差异(P均0.05)。结论：1.DAT1及DRD4基因启动子区CpG岛甲基化状态可能与ADHD易感性相关；2.不同性别、年龄DAT1及DRD4基因启动子区CpG岛甲基化状态存在差异；3.DAT1基因启动子区甲基化水平可能影响ADHD患者对立违抗行为的严重程度。
[Abstract]:Objective: to explore the difference of methylation status between children with attention deficit hyperactivity disorder (ADHDD) and normal children in the promoter of dopamine transporter gene (DAT1 / SLC6A3) and dopamine D4 receptor gene (DRD4) promoter.To understand the correlation between the level of DAT1 DRD4 methylation and the severity of clinical symptoms in children with ADHD, the purpose of this study was to further understand and elucidate the genetic mechanism of ADHD from the perspective of epigenetics.And the relationship between clinical symptoms and methylation level of dopamine neurotransmitter system.Methods: the peripheral blood and general demographic data of 111 ADHD patients and 118 control children were collected, and the clinical symptoms, cognitive function and family history of 111 patients with ADHD were evaluated.Sodium bisulfite sequencing was used to determine the methylation status of each CpG site in the CpG island of the promoter region of the DAT1 gene in 111 ADHD patients and 118 control children.Results there was no significant difference between the case group and the control group in the frequency of total methylation in the promoter region of DAT1 and DRD4 gene. There was no significant difference between the two groups in the CpG island fragment of the promoter region of P0.05DAT1 gene.The frequency of methylation in the 17th CpG locus group was higher than that in the control group, and in the CpG island fragment of the promoter region of the DRD4 gene, the frequency of methylation was higher than that in the control group.The frequency of methylation in the eighth CpG locus group was higher than that in the control group. The frequency of methylation in the promoter region of DAT1 gene was higher in males than in females, and the frequency of methylation in promoter region of DRD4 gene was higher in males than in females.The frequency of methylation in the promoter region of DAT1 gene was higher in the male than in the female, and the frequency of methylation in the promoter of the DRD4 gene in the control group was higher than that in the male.In all the samples, the frequency of methylation in the promoter region of DAT1 gene was higher in the age group of 7 years old than that in the group of 1-7 years old, and in the age group of 7 years old, the frequency of methylation in the promoter region of the DAT1 gene group was higher than that in the group of 1-7 years old, and that in the age group of 7 years old was higher than that in the group of 1-7 years old.The frequency of methylation in the promoter region of DAT1 gene in the 4-year course group was higher than that in the ADHD group with a duration of 1-4 years (P0.05. 4).In the case group, the frequency of methylation in the DAT1 promoter was higher in the patients without depression and anxiety than in the patients with a family history (P 0.05. 5).In the case group, the proportion of DAT1 gene methylation frequency in children with oppositional defiant disorder (ODD9) scores was higher than those with ODD 鈮，

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