色氨酸羟化酶2基因rs4570625和rs4565946与抽动秽语综合征的相关性研究

Association of single nucleotide polymorphisms （rs4565946 and rs4570625） of tryptophan hydroxylase2 gene with Tourette＇s syndrome

目的 探讨色氨酸羟化酶2（TPH2）基因单核苷酸多态性（SNPs）与北京地区汉族抽动秽语综合征（TS）患儿发病的关系. 方法 选择首都儿科研究所神经科门诊自2009年1月至2011年1月诊治的TS患儿149例作为病例组,其中112例男性患儿按耶鲁综合抽动严重程度量表（YGTSS）评分分为轻症组（25例）、中重度组（87例）.以同期在北京市体检中心体检的125例正常儿童作为对照组.应用MassARRAY SNPs质谱基因分型法检测2组外周血基因组DNA样本TPH2基因2个SNPs（rs4570625、rs4565946）,比较各组基因型的分布及等位基因的频率;应用生物信息学方法对TPH2基因2个SNPs进行分析和功能预测. 结果病例组及对照组rs4565946位点基因型频率分布比较差异有统计学意义（P＜0.05）,TT基因型相对CC＋CT基因型频率分布比较差异有统计学意义（P＜0.05）,OR值为3.077（95％CI：1.273～7.437）.病例组男性与对照组男性比较rs4570625等位基因频率比较差异有统计学意义（P＜0.05）; TT基因型相对CC＋CT基因型频率分布比较差异有统计学意义（P＜0.05）,OR值为3.228（95％CI：1.153～9.040）.与对照组男性比较,TS男性患儿中重度组rs4570625位点等位基因频率比较差异有统计学意义（P＜0.05）.生物信息学分析发现TPH2基因rs4570625野生型T等位基因突变为G后影响了转录因子与该基因启动子的结合. 结论 TPH2基因rs4565946、rs4570625可能与北京地区汉族TS患儿的易感性有关;rs4565946 TT基因型会增加TS的发病风险;rs4570625 G等位基因与男性TS抽动症状严重程度有关.

Objective To investigate the association of single nucleotide polymorphisms （SNPs,rs4565946 and rs4570625） of tryptophan hydroxylase2 （TPH2） gene with Tourette＇s syndrome （TS） in Beijing Han population.Methods One hundred and forty-nine patients with TS,diagnosed and treated in our hospital from January 2009 to January 2011,were chosen; these patients were sub-divided into mild symptoms group （n=25） and moderate to severe symptoms group （n=87） according to the scores of Yale Global Tic Severity Scale （YGTSS）; another 125 healthy children,collected at the same time period,were used as control group.MassARRAY iPLEX GOLD System was used to detect the two SNPs （rs4570625 and rs4565946） of TPH2 gene.Genotype distribution and allele fiequencies of these two group patients were compared.Transcription factor binding sites of TPH2 gene polymorphisms were analyzed by the web site of transcription factor binding sites for function prediction.Results For rs4565946,individuals with the TT genotype showed a significantly higher risk of TS than those with TC plus CC genotypes （OR=3.077,95%CI：1.273-7.437; P〈0.05）; as did male TS children with the TT genotype （OR=3.228,95% CI：1.153-9.040; P〈0.05）.Further association analyses showed that G allele of rs4570625 in children of moderate to severe symptoms group had significantly higher frequency than that in controls among the male children （OR=1.684,95%：1.097-2.583; P〈0.05）.Children of moderate to severe symptoms group had significantly higher frequencies of rs4546946 TT genotype than normal controls in males （OR=3.292,95% CI：1.139-9.513; P〈0.05）.Bioinformatics method indicated that the G genotype of rs4570625 mutated from T genotype might affect the binding ability of its transcription factor with its promoter in TPH2 gene.Conclusions TT genotype of rs4565946 is a potential genetic risk factor for TS.Allele G ofrs4570625 might be associated with the severity of tic symptoms in boys.These polymorphisms might be susceptibility loci for TS.