应用磁共振T_2弛豫自旋标记技术研究多巴胺D4受体-616位点单核苷酸多态性对原发性夜间遗尿症患儿脑氧代谢的影响
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摘要
目的:应用T_2弛豫自旋标记(TRUST)技术,探讨多巴胺D4受体基因(DRD4)616位点(rs747302)单核苷酸多态性(Single nucleotide polymorphism,SNP)对原发性夜间遗尿症(Primary nocturnal enuresis,PNE)患儿脑氧代谢的影响。方法:本研究为前瞻性研究,通过DRD4-616位点基因型检测及TRUST扫描,获取2016年2月—2017年12月56例PNE患儿及58例正常对照组儿童的脑氧代谢数据及基因型数据。以年龄、性别作为协变量,以分组(PNE/对照)及基因型(C/G)作为可能的影响因素,针对脑氧摄取率(Oxygen extraction fraction,OEF)以及脑氧代谢率(Cerebral metabolic rate of oxygen,CMRO2)进行析因设计的协方差分析。结果:OEF以及CMRO2分组×基因型交互效应显著(F_(1,110)=6.513,P=0.012 1;F_(1,110)=6.888,P<0.001;F_(1,110)=13.01,P<0.001),Post-Hoc检验发现结果携带C等位基因的PNE患儿OEF以及CMRO2值显著低于G纯合子PNE患儿(t=-5.976,Padjusted<0.001;t=-5.594,Padjusted<0.001);Yν显著高于G纯合子PNE患儿(t=5.863,Padjusted<0.001)。结论 :DRD4-616 SNP对于PNE患儿OEF及CMRO2造成了影响,这可能与PNE的发病有关。
Objective: To determine whether the 616 C/G single nucleotide polymorphism(SNP) in the dopamine D4 receptor(DRD4) promoter rs747302 was associated with abnormal whole-brain cerebral metabolic rate of oxygen(CMRO_2), cerebral blood flow(CBF) and oxygen extraction fraction(OEF) in children that suffer from primary nocturnal enuresis(PNE) using T_2-relaxation-under-spin-tagging(TRUST) methodology. Methods: Genomic and TRUST imaging data were obtained from 56 PNE pediatric patients and 58 healthy controls. SNP of rs747302 was genotyped. TRUST imaging data were collected on a 3.0-Tesla MR scanner, OEF and CMRO_2 data were calculated using an in-house package. OEF and CMRO_2 were compared between different group(PNE/control) and genotype(C/G) using two-way ANCOVA analysis. Results: Group-genotype interactions were found in OEF and CMRO_2, post-hoc testing demonstrated that the C-allele carriers in the PNE group had a significantly increased OEF and CMRO_2. Conclusion: Among PNE children, C-allele carriers of rs747302 are associated with abnormal OEF and CMRO_2.
Objective: To determine whether the 616 C/G single nucleotide polymorphism(SNP) in the dopamine D4 receptor(DRD4) promoter rs747302 was associated with abnormal whole-brain cerebral metabolic rate of oxygen(CMRO_2), cerebral blood flow(CBF) and oxygen extraction fraction(OEF) in children that suffer from primary nocturnal enuresis(PNE) using T_2-relaxation-under-spin-tagging(TRUST) methodology. Methods: Genomic and TRUST imaging data were obtained from 56 PNE pediatric patients and 58 healthy controls. SNP of rs747302 was genotyped. TRUST imaging data were collected on a 3.0-Tesla MR scanner, OEF and CMRO_2 data were calculated using an in-house package. OEF and CMRO_2 were compared between different group(PNE/control) and genotype(C/G) using two-way ANCOVA analysis. Results: Group-genotype interactions were found in OEF and CMRO_2, post-hoc testing demonstrated that the C-allele carriers in the PNE group had a significantly increased OEF and CMRO_2. Conclusion: Among PNE children, C-allele carriers of rs747302 are associated with abnormal OEF and CMRO_2.
引文
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[7]Lu H, Xu F, Grgac K, et al. Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation[J].Magn Reson Med, 2012, 67(1):42-49.
[8]Liu P, Dimitrov I, Andrews T, et al. Multisite evaluations of a T2-relaxation-under-spin-tagging(TRUST)MRI technique to measure brain oxygenation[J]. Magn Reson Med, 2016, 75(2):680-687.
[9]Williams T, Tjian R. Characterization of a dimerization motifin AP-2 and its function in heterologous DNA-binding proteins[J].Science, 1991, 251(4997):1067-1071.
[10]Wang X, Zhong P, Gu Z, et al. Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex[J]. J Neurosci,2003, 23(30):9852-9861.
[11]Gu Z, Yan Z. Bidirectional regulation of Ca2+calmodulindependent protein kinaseⅡactivity by dopamine D4 receptors in prefrontal cortex[J]. Mol Pharmacol, 2004, 66(4):948-955.
[12]Esposito M, Gallai B, Parisi L, et al. Primary nocturnal enuresis as a risk factor for sleep disorders:an observational questionnaire-based multicenter study[J]. Neuropsychiatr Dis Treat, 2013, 9:437-443.
[2]Wei CC, Wan L, Lin WY, et al. Rs 6313 polymorphism in 5-hydroxytryptamine receptor 2A gene association with polysymptomatic primary nocturnal enuresis[J]. J Clin Lab Anal, 2010, 24(6):371-375.
[3]戴晓梅,麻宏伟,卢瑶,等.多巴胺D4受体基因多态性与原发性夜间遗尿症的关联研究[J].中国当代儿科杂志,2008,10(5):607-610.
[4]Ge Y, Zhang Z, Lu H, et al. Characterizing brain oxygen metabolism in patients with multiple sclerosis with T2-relaxationunder-spin-tagging MRI[J]. J Cereb Blood Flow Metab, 2012, 32(3):403-412.
[5]Xu F, Ge Y, Lu H. Noninvasive quantification of whole-brain cerebral metabolic rate of oxygen(CMRO2)by MRI[J]. Magn Reson Med, 2009, 62(1):141-148.
[6]von Gontard A. The impact of DSM-5 and guidelines for assessment and treatment of elimination disorders[J]. Eur Child Adol Psych, 2013, 22(Suppl 1):61-67.
[7]Lu H, Xu F, Grgac K, et al. Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation[J].Magn Reson Med, 2012, 67(1):42-49.
[8]Liu P, Dimitrov I, Andrews T, et al. Multisite evaluations of a T2-relaxation-under-spin-tagging(TRUST)MRI technique to measure brain oxygenation[J]. Magn Reson Med, 2016, 75(2):680-687.
[9]Williams T, Tjian R. Characterization of a dimerization motifin AP-2 and its function in heterologous DNA-binding proteins[J].Science, 1991, 251(4997):1067-1071.
[10]Wang X, Zhong P, Gu Z, et al. Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex[J]. J Neurosci,2003, 23(30):9852-9861.
[11]Gu Z, Yan Z. Bidirectional regulation of Ca2+calmodulindependent protein kinaseⅡactivity by dopamine D4 receptors in prefrontal cortex[J]. Mol Pharmacol, 2004, 66(4):948-955.
[12]Esposito M, Gallai B, Parisi L, et al. Primary nocturnal enuresis as a risk factor for sleep disorders:an observational questionnaire-based multicenter study[J]. Neuropsychiatr Dis Treat, 2013, 9:437-443.