福建地区Tourette综合征DRD4基因第3外显子48bpVNTR多态性研究
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摘要
目的:探讨福建儿童和青少年中Tourette综合征与DRD4基因第3号外显子48bpVNTR多态性的关系。
方法:研究对象包括118名正常人和106例Tourette综合征。采用抽提人基因组DNA、聚合酶链反应、琼脂糖凝胶电泳,结合PAGE胶电泳及银染技术检测DRD4基因第3外显子48bpVNTR多态性的等位基因和基因型。部分有代表性等位基因片段的PCR产物直接测序,检测其基因型。将TS患者与正常人的DRD4基因型进行对比,采用x~2检验分析其与TS的相关性。
结果:DRD4基因48bpVNTR多态性根据所含可变串联重复序列数目不同,分为不同的基因型。
1、对224个个体检测的结果可见到8种基因型,分别为2/2、2/3、2/4、2/5、3/4、4/4、4/5、4/6。
2、DRD4基因型分布:患病组及对照组最多见4/4基因型,其次为2/4基因型,但经比较两组间总体分布有显著性差异(P＜0.01)。
3、DRD4等位基因频率分布:DRD4 48bpVNTR有5种等位基因,即对应为2～6次重复。患病组及对照组最多见DRD4~*4R等位基因,其次为DRD4~*2R等位基因,但经比较两组间差异有显著性(P＜0.01)。
4、DRD4 48bpVNTR长短重复等位基因的比较:将DRD4 48bpVNTR等位基因分为长重复等位基因(≥5个48 bp重复等位基因)和短重复等位基因(＜5个48 bp重复等位基因),患病组与对照组比较差异有显著性(P＜0.05)。
结论:本研究发现,福建地区TS组与正常对照组中,DRD4 48bpVNTR共检测到8种基因型,分别是2/2、2/3、2/4、2/5、3/4、4/4、4/5、4/6;有5种等位基因,即对应为2～6次重复。TS组与正常对照组中,DRD4 48bpVNTR基因型总体分布趋势有显著性差异(P＜0.01)。两组间DRD4等位基因频率分布存在显著性差异(P＜0.01)。对于DRD4 48bpVNTR长短重复等位基因的比较,患病组与对照组亦有显著性差异(P＜0.05)。由此推断,DRD4第3号外显子的48bpVNTR多态性可能与福建地区TS有关联。
Objective To study the relationship between Tourette syndrome and the dopaminereceptor-4 gene exon3 48bp VNTR polymorphism in children from Fujian region.
Methods The genotypes and alleles of 118 normal controls and 106 children withTS were detected by polymerase chain reaction, denaturing polyacry lamide gelelectrophorsis and silver staining. Some of them were directly sequenced to examinethe genotypes. The 48bp VNTR alleles and genotypes of patients with TS and controlswere compared by chi square test.
Results 1.Eight genotypes were found in 224 individuals based on different 48bpVNTR alleles, which were 2/2、2/3、2/4、2/5、3/4、4/4、4/5、4/6.
2.DRD4 genotypes distribution :The most common genotype was 4/4.There wasstatistically significant difference in genotype distribution between TS group andcontrol group(X~2 = 19.564, P<0.01).
3.DRD4 alleles frequency distribution : five alleles were found, the repeat numbers of48bp were 2 to 6. The common unit was 4-repeat allele. There was statisticallysignificant difference in allele frequency distribution between TS group and normalcontrol group(X~2 = 16.168, P<0.01).
4.Contrasting DRD4 48bp VNTR longer allele with shorter allele: When the DRD448bp VNTR was divided into " longer allele"(≥5 repeats) and "shorter allele"(<5repeats), statistically significant differences of both longer and shorter alleles werefound in both groups(X~2=4.0581, P<0.05).
Conclusions In this study, we found eight genotypes and five alleles of DRD4 48bpVNTR.There were statistically significant differences in genotype distribution, allelefrequency, contrasting longer allele with shorter allele between TS group and controlgroup.Thus we concluded that DRD4 48bp VNTR polymorphism maybe beassociated with TS in Fujian region.
方法:研究对象包括118名正常人和106例Tourette综合征。采用抽提人基因组DNA、聚合酶链反应、琼脂糖凝胶电泳,结合PAGE胶电泳及银染技术检测DRD4基因第3外显子48bpVNTR多态性的等位基因和基因型。部分有代表性等位基因片段的PCR产物直接测序,检测其基因型。将TS患者与正常人的DRD4基因型进行对比,采用x~2检验分析其与TS的相关性。
结果:DRD4基因48bpVNTR多态性根据所含可变串联重复序列数目不同,分为不同的基因型。
1、对224个个体检测的结果可见到8种基因型,分别为2/2、2/3、2/4、2/5、3/4、4/4、4/5、4/6。
2、DRD4基因型分布:患病组及对照组最多见4/4基因型,其次为2/4基因型,但经比较两组间总体分布有显著性差异(P＜0.01)。
3、DRD4等位基因频率分布:DRD4 48bpVNTR有5种等位基因,即对应为2～6次重复。患病组及对照组最多见DRD4~*4R等位基因,其次为DRD4~*2R等位基因,但经比较两组间差异有显著性(P＜0.01)。
4、DRD4 48bpVNTR长短重复等位基因的比较:将DRD4 48bpVNTR等位基因分为长重复等位基因(≥5个48 bp重复等位基因)和短重复等位基因(＜5个48 bp重复等位基因),患病组与对照组比较差异有显著性(P＜0.05)。
结论:本研究发现,福建地区TS组与正常对照组中,DRD4 48bpVNTR共检测到8种基因型,分别是2/2、2/3、2/4、2/5、3/4、4/4、4/5、4/6;有5种等位基因,即对应为2～6次重复。TS组与正常对照组中,DRD4 48bpVNTR基因型总体分布趋势有显著性差异(P＜0.01)。两组间DRD4等位基因频率分布存在显著性差异(P＜0.01)。对于DRD4 48bpVNTR长短重复等位基因的比较,患病组与对照组亦有显著性差异(P＜0.05)。由此推断,DRD4第3号外显子的48bpVNTR多态性可能与福建地区TS有关联。
Objective To study the relationship between Tourette syndrome and the dopaminereceptor-4 gene exon3 48bp VNTR polymorphism in children from Fujian region.
Methods The genotypes and alleles of 118 normal controls and 106 children withTS were detected by polymerase chain reaction, denaturing polyacry lamide gelelectrophorsis and silver staining. Some of them were directly sequenced to examinethe genotypes. The 48bp VNTR alleles and genotypes of patients with TS and controlswere compared by chi square test.
Results 1.Eight genotypes were found in 224 individuals based on different 48bpVNTR alleles, which were 2/2、2/3、2/4、2/5、3/4、4/4、4/5、4/6.
2.DRD4 genotypes distribution :The most common genotype was 4/4.There wasstatistically significant difference in genotype distribution between TS group andcontrol group(X~2 = 19.564, P<0.01).
3.DRD4 alleles frequency distribution : five alleles were found, the repeat numbers of48bp were 2 to 6. The common unit was 4-repeat allele. There was statisticallysignificant difference in allele frequency distribution between TS group and normalcontrol group(X~2 = 16.168, P<0.01).
4.Contrasting DRD4 48bp VNTR longer allele with shorter allele: When the DRD448bp VNTR was divided into " longer allele"(≥5 repeats) and "shorter allele"(<5repeats), statistically significant differences of both longer and shorter alleles werefound in both groups(X~2=4.0581, P<0.05).
Conclusions In this study, we found eight genotypes and five alleles of DRD4 48bpVNTR.There were statistically significant differences in genotype distribution, allelefrequency, contrasting longer allele with shorter allele between TS group and controlgroup.Thus we concluded that DRD4 48bp VNTR polymorphism maybe beassociated with TS in Fujian region.
引文
1.Apter A,Pauls DL,Bleich A,et al.An epidemiologic syudy of Gilles de la Tourette's syndrome in Israle.Arch Gen Psychiatry,1993,50:734-738.
2.李大年主编.现代神经内科学.第一版.济南:山东科学技术出版社,2002.
3.Singer HS,Minzer K.Neurobiology of Tourette's syndrome:concepts of neuroanatomic localization and neurochemical abnormalities.Brain Dev Suppl,2003,25:70-84.
4.Grice DE,Leckman JF,Pauls DL,et al.Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette Syndrome,by the mmsmission-disequilibrium test.Am J Hum Genet,1996,59:644-652
5.Chang FM,Kidd JR,Livak K J,et all The world2wide distribution of allele frequencies at human dopamine 4 receptor locusl Hum Genet,1996,98:90-91.
6.Guo ZM,Wu KM,Shang J,et al.Correlated research between DRD4 gene 48bp VNTR polymorphism in the third exon and toddler temperament.Chin J Med Genet,2002,19:536-538.[郭贞美,吴康敏,尚佳,等.DRD4第3外显子48bp可变重复序列多态性与幼儿气质的相关研究.中华医学遗传学杂志,2002,19:536-538.]
7.Lu Z,Cai J,Wang DX,et al.An analysis of association between dopamine D4receptor gene and apolipoprotein E gene and schizophrenia.Chin J Psychiatry,2003,36:17-20.[陆峥,蔡军,汪栋祥,等.精神分裂症与多巴胺D4受体基因及载脂蛋白E基因的关联分析.中华精神科杂志,2003,36:17-20.]
8.Tang YL,Wang YF,Cai ZJ,et al.Schizophrenia and dopamine D4genepopymorphism in Chinese population:association analysis.Natl Med J China,2001,81:995-998.[汤宜朗,王凤,蔡焯基,等.精神分裂症与多巴胺D4受体基因多态性的关联分析.中华医学杂志,2001,81:995-998.]
9.Casba Barta,Zsolt Ronai,Zsolt Nemoda,et al.Analysis of dopamine D4 receptor gene polymorphism using microchip electrophoresis.Journal of Chromatography A,2001,924:285-290.
10.仲爱芳,汪广剑,孙芳卿.抽动秽语综合征与多巴胺受体系统基因的关系[J].临床精神医学杂志,2001,11(5):294-295.
11.Pauls,David L.An update on the genetics of Gilles de la Tourette syndrome.Joumal of Psychosomatic Research,2003,55:7-6.
12.Sibly DR,Monama FJ.Molecular biology of dopamine receptors.Treads Pharmacol Sci,1992,13:61-69.
13.Wahles WP,Wallace LJ,Moore PD.Hypervariable ministellite DNA is a hotspot for homologous recombination in human cells.Cell,1990,60:95-103.
14.程宇航,郑毅,王力芳等.抽动秽语综合征的多巴胺D4受体基因多态性分析.中华检验医学杂志,2003,26(1):40-41.
15.Huang Y,Li T,Wang Y,et al.Linkage disequilibrium analysis ofpolymorphisms in the gene for myelin oligodendrocyte glycoprotein in Tourette's syndrome patients from a Chinese sample.Am J Med Genet B Neuropsychiatr Genet.2004Jan 1;124(1):76-80.
16.Diaz-Anzaldua A,Joober R,Riviere JB,et al.Tourette syndrome and dopaminergic genes:a family-based association study in the French Canadian founder population.Mol Psychiatry.2004 Mar;9(3):272-7.
17.赵爱玲,赵靖平,张玉虎等.湖南地区汉族人多巴胺D4受体基因48 bp可变数目串联重复多态性分布.中华医学遗传学杂志,2005,22(4):470-472.
18.黄颐,刘协和,郭兰婷等.多巴胺D4受体第3外显子48 bp可变重复序列多态性与抽动障碍的关联分析.中华精神科杂志,2001,34(1):23-26.
1.李大年主编.现代神经内科学.第一版.济南:山东科学技术出版社,2002
2.Kano Y,Ohta M,Nagai Y,et al.A family study of Tourttte syndrome in Japan.Am J Med Genet,2001,105(5):414
3.杨宏宇,皇甫恩,谭庆荣.抽动秽语综合征的遗传学研究进展.国外医学精神病学分册,2001,28,(4):239
4.Kroisel PM,Petek E,Emberger W,et al.Candidate region for Gilles de la Tourette syndrome at 7q31.Am J Med Genet.2001 Jul 1;101(3):259-61.
5.Diaz-Anzaldua A,Joober R,Riviere JB,et al.Association between 7q31 markers and Tourette syndrome.Am J Med Genet A.2004 May 15;127(1):17-20.
6.Cuker A,State MW,King RA,et al.Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/chronic tic disorder at 18q22.Am J Med Genet A.2004 Sep 15;130(1):37-9.
7.Crawford FC,Ait-Ghezala G,Morris M,et al.Translocation breakpoint in two unrelated Tourette syndrome cases,within a region previously linked to the disorder.Hum Genet.2003 Jul;113(2):154-61.Epub 2003 Apr 16.
8 Verkerk,A.J.M.H.;Mathews,C.A.;Joosse,M.;Eussen,B.H.J.;Heutink,P.;Oostra,B.A.:The Tourette Syndrome Association International Consortium for Genetics:CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder.Genomics 82:1-9,2003.
9.Diaz-Anzaldua A,Riviere JB,Dube MP,et al.Chromosome 11-q24 region in Tourette syndrome:association and linkage disequilibrium study in the French Canadian population.:Am J Med Genet A.2005 Oct 15;138(3):225-8
10.Abelson JF,Kwan KY,O'Roak BJ,et al.Sequence variants in SLITRK1 are associated with Tourette's syndrome.Science.2005 Oct 14;310(5746):317-20.
11.Paschou P,Feng Y,Pakstis AJ,et al.Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples:17q25 is a putative susceptibility region.Am J Hum Genet.2004 Oct;75(4):545-60.Epub 2004 Aug 9.
12.刘道宽等主编.锥体外系疾病.上海:上海科学技术出版社,2000,328-330
13.仲爱芳,汪广剑,孙芳卿.抽动秽语综合征与多巴胺受体系统基因的关系[J].临床精神医学杂志,2001,11(5):294-295.
14.Comings DE,Crade R,Wu S,et al.Studies of the potential role of the dopamine D_1receptor gene in addictive behaviors.Mol Psychiatry.1997.2:44
15.Chou IC,Tsai CH,Lee CC,et al.Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children.Psychiatr Genet.2004 Dec;14(4):219-21.
16.Lee CC,Chou IC,Tsai CH,et al.Dopamine receptor D2 gene polymorphisms are associated in Taiwanese children with Tourette syndrome.Pediatr Neurol.2005 Oct;33(4):272-6.
17.Nothen MM,Hebebrand J,Knapp M,et al.Association analysis of the dopamine D_2receptor gene in Tourtette syndrome using the haplotype relative method.Am J Med Gener;1994,54:29
18.程宇航,郑毅,王力芳等.抽动秽语综合征的多巴胺D4受体基因多态性分析.中华检验医学杂志,2003,26(1):40-41
19.Huang Y,Li T,Wang Y,et al.Linkage disequilibrium analysis of polymorphisms in the gene for myelin oligodendrocyte glycoprotein in Tourette's syndrome patients from a Chinese sample.Am J Med Genet B Neuropsychiatr Genet.2004Jan 1;124(1):76-80.
20.Diaz-Anzaldua A,Joober R,Riviere JB,et al.Tourette syndrome and dopaminergic genes:a family-based association study in the French Canadian founder population.Mol Psychiatry.2004 Mar;9(3):272-7.
21.Barr CL,Wigg KG;Zoko E,et al.No evidence for amajior gene effect of the dopamine D_4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families.Am J Mde Genet,1996,67:301
22.Catalaao M,Sciuto G,Di Bella D.et al.Lack ol association betwee～obseccive--compu]sire disorder and the dopamine D3 receptorgene=Some preliminary cosideration Am J Med Genet, 1994, 54: 253
23. Barr CL, Wijj KG, Zovko E, et al The Bal I and MSP I polymorphisms in the dopamine D, receptor gene display, linkage disequilibrium with each other but no association with TouretteSyndrome. Am J Med Genet. 1990, 07: 301
24. Barr CL, Wigg KG, Zovko E, et al. Linkage study of thedopamine D_5 receptor gene and Gelles de la TouTe rte syndrome. Am J Med Genet, 1997, 74: 58
25. Schoenian S, Konig I, Oertel W,et al.HLA-DRB genotyping in Gilles de la Tourette patients and their parents.Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119(1):60-4.
26. Niesler B, Frank B, Hebebrand J,et al. Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome.Psychiatr Genet. 2005 Dec;15(4):303-4.
27. de Carvalho Aguiar P, Fazzari M, Jankovic J,et al. Examination of the SGCE gene in Tourette syndrome patients with obsessive-compulsive disorder.Mov Disord. 2004 Oct;19(10):1237-8.
2.李大年主编.现代神经内科学.第一版.济南:山东科学技术出版社,2002.
3.Singer HS,Minzer K.Neurobiology of Tourette's syndrome:concepts of neuroanatomic localization and neurochemical abnormalities.Brain Dev Suppl,2003,25:70-84.
4.Grice DE,Leckman JF,Pauls DL,et al.Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette Syndrome,by the mmsmission-disequilibrium test.Am J Hum Genet,1996,59:644-652
5.Chang FM,Kidd JR,Livak K J,et all The world2wide distribution of allele frequencies at human dopamine 4 receptor locusl Hum Genet,1996,98:90-91.
6.Guo ZM,Wu KM,Shang J,et al.Correlated research between DRD4 gene 48bp VNTR polymorphism in the third exon and toddler temperament.Chin J Med Genet,2002,19:536-538.[郭贞美,吴康敏,尚佳,等.DRD4第3外显子48bp可变重复序列多态性与幼儿气质的相关研究.中华医学遗传学杂志,2002,19:536-538.]
7.Lu Z,Cai J,Wang DX,et al.An analysis of association between dopamine D4receptor gene and apolipoprotein E gene and schizophrenia.Chin J Psychiatry,2003,36:17-20.[陆峥,蔡军,汪栋祥,等.精神分裂症与多巴胺D4受体基因及载脂蛋白E基因的关联分析.中华精神科杂志,2003,36:17-20.]
8.Tang YL,Wang YF,Cai ZJ,et al.Schizophrenia and dopamine D4genepopymorphism in Chinese population:association analysis.Natl Med J China,2001,81:995-998.[汤宜朗,王凤,蔡焯基,等.精神分裂症与多巴胺D4受体基因多态性的关联分析.中华医学杂志,2001,81:995-998.]
9.Casba Barta,Zsolt Ronai,Zsolt Nemoda,et al.Analysis of dopamine D4 receptor gene polymorphism using microchip electrophoresis.Journal of Chromatography A,2001,924:285-290.
10.仲爱芳,汪广剑,孙芳卿.抽动秽语综合征与多巴胺受体系统基因的关系[J].临床精神医学杂志,2001,11(5):294-295.
11.Pauls,David L.An update on the genetics of Gilles de la Tourette syndrome.Joumal of Psychosomatic Research,2003,55:7-6.
12.Sibly DR,Monama FJ.Molecular biology of dopamine receptors.Treads Pharmacol Sci,1992,13:61-69.
13.Wahles WP,Wallace LJ,Moore PD.Hypervariable ministellite DNA is a hotspot for homologous recombination in human cells.Cell,1990,60:95-103.
14.程宇航,郑毅,王力芳等.抽动秽语综合征的多巴胺D4受体基因多态性分析.中华检验医学杂志,2003,26(1):40-41.
15.Huang Y,Li T,Wang Y,et al.Linkage disequilibrium analysis ofpolymorphisms in the gene for myelin oligodendrocyte glycoprotein in Tourette's syndrome patients from a Chinese sample.Am J Med Genet B Neuropsychiatr Genet.2004Jan 1;124(1):76-80.
16.Diaz-Anzaldua A,Joober R,Riviere JB,et al.Tourette syndrome and dopaminergic genes:a family-based association study in the French Canadian founder population.Mol Psychiatry.2004 Mar;9(3):272-7.
17.赵爱玲,赵靖平,张玉虎等.湖南地区汉族人多巴胺D4受体基因48 bp可变数目串联重复多态性分布.中华医学遗传学杂志,2005,22(4):470-472.
18.黄颐,刘协和,郭兰婷等.多巴胺D4受体第3外显子48 bp可变重复序列多态性与抽动障碍的关联分析.中华精神科杂志,2001,34(1):23-26.
1.李大年主编.现代神经内科学.第一版.济南:山东科学技术出版社,2002
2.Kano Y,Ohta M,Nagai Y,et al.A family study of Tourttte syndrome in Japan.Am J Med Genet,2001,105(5):414
3.杨宏宇,皇甫恩,谭庆荣.抽动秽语综合征的遗传学研究进展.国外医学精神病学分册,2001,28,(4):239
4.Kroisel PM,Petek E,Emberger W,et al.Candidate region for Gilles de la Tourette syndrome at 7q31.Am J Med Genet.2001 Jul 1;101(3):259-61.
5.Diaz-Anzaldua A,Joober R,Riviere JB,et al.Association between 7q31 markers and Tourette syndrome.Am J Med Genet A.2004 May 15;127(1):17-20.
6.Cuker A,State MW,King RA,et al.Candidate locus for Gilles de la Tourette syndrome/obsessive compulsive disorder/chronic tic disorder at 18q22.Am J Med Genet A.2004 Sep 15;130(1):37-9.
7.Crawford FC,Ait-Ghezala G,Morris M,et al.Translocation breakpoint in two unrelated Tourette syndrome cases,within a region previously linked to the disorder.Hum Genet.2003 Jul;113(2):154-61.Epub 2003 Apr 16.
8 Verkerk,A.J.M.H.;Mathews,C.A.;Joosse,M.;Eussen,B.H.J.;Heutink,P.;Oostra,B.A.:The Tourette Syndrome Association International Consortium for Genetics:CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder.Genomics 82:1-9,2003.
9.Diaz-Anzaldua A,Riviere JB,Dube MP,et al.Chromosome 11-q24 region in Tourette syndrome:association and linkage disequilibrium study in the French Canadian population.:Am J Med Genet A.2005 Oct 15;138(3):225-8
10.Abelson JF,Kwan KY,O'Roak BJ,et al.Sequence variants in SLITRK1 are associated with Tourette's syndrome.Science.2005 Oct 14;310(5746):317-20.
11.Paschou P,Feng Y,Pakstis AJ,et al.Indications of linkage and association of Gilles de la Tourette syndrome in two independent family samples:17q25 is a putative susceptibility region.Am J Hum Genet.2004 Oct;75(4):545-60.Epub 2004 Aug 9.
12.刘道宽等主编.锥体外系疾病.上海:上海科学技术出版社,2000,328-330
13.仲爱芳,汪广剑,孙芳卿.抽动秽语综合征与多巴胺受体系统基因的关系[J].临床精神医学杂志,2001,11(5):294-295.
14.Comings DE,Crade R,Wu S,et al.Studies of the potential role of the dopamine D_1receptor gene in addictive behaviors.Mol Psychiatry.1997.2:44
15.Chou IC,Tsai CH,Lee CC,et al.Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children.Psychiatr Genet.2004 Dec;14(4):219-21.
16.Lee CC,Chou IC,Tsai CH,et al.Dopamine receptor D2 gene polymorphisms are associated in Taiwanese children with Tourette syndrome.Pediatr Neurol.2005 Oct;33(4):272-6.
17.Nothen MM,Hebebrand J,Knapp M,et al.Association analysis of the dopamine D_2receptor gene in Tourtette syndrome using the haplotype relative method.Am J Med Gener;1994,54:29
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