中文摘要：

目的分析TBX2基因3＇UTR变异位点与汉族人群散发型先天性心脏病（CHD）的遗传易感性是否关联,初步探讨其可能的发病机制。方法纳入2010年8月至2012年4月山东济南军区总医院心血管病研究所诊断的非综合征型汉族CHD为CHD组,以同期医院和社区体检的健康儿童为对照组。选择CHD组和对照组各24例行TBX2 3＇UTR测序。根据测序结果在CHD组和对照组分别行SNa Pshot基因分型和关联分析;通过细胞转染及荧光素酶检测对阳性位点进行功能分析。结果 CHD组纳入768例,年龄（6.1±4.8）岁,男383例（49.9%）;对照组纳入660例,年龄（6.5±3.2）岁,男354例（53.6%）。124例CHD和24例对照行TBX2基因3＇UTR区测序发现3个已知的SNPs位点：rs59382073、rs1058004和rs729782,未检出新发SNPs位点。2样本采集中期CHD和对照组各288例样本的关联分析显示,rs59382073的基因型在CHD组和对照组的分布差异有统计学意义（P=0.012）;余2个SNPs在两组间差异无统计学意义（P〉0.5）,后续样本未行该2个SNPs检测。3全样本关联分析显示,TBX2 3＇UTR rs59382073位点与散发型CHD的患病风险密切相关,GT/TT基因型较GG基因型可导致CHD的患病风险增加2.13倍（OR=2.13,95%CI：1.51~2.99,P=1.44×10-5）;进一步分层分析显示,与GG基因型相比,GT/TT基因型增加2.75倍圆椎动脉干畸形（OR=2.75,95%CI：1.57~4.81,P=3.99×10-4）、3.18倍法洛四联症（OR=3.18,95%CI：1.53~6.61,P=1.90×10-3）和1.70倍室间隔缺损（OR=1.70,95%CI：1.17~2.46,P=5.14×10-3）的患病风险。4细胞水平的功能研究提示,与G等位基因相比,转染T等位基因可分别导致HEK293 T及H9C2细胞的荧光素酶活性下降29.2%和33.6%。结论 TBX2 3＇UTR rs59382073位点可显著增加汉族人群散发型CHD的患病风险;其不同等位基因的荧光素酶表达水平存在差异,为潜在的功能位点。

英文摘要：

Objective To investigate the association between TBX2 3＇UTR variants and the susceptibility of sporadic congenital heart disease（ CHD） in Chinese Han population and to reveal the possible mechanism. Methods Patients with non-syndromic CHD diagnosed in Institute of Cardiovascular Disease,General Hospital of Ji＇nan Military Region from August 2010 to April 2012 were included in CHD group,and healthy children receiving physical examination in this hospital during the same period as the control group. Twenty-four CHD cases and the same number of controls were selected to undergo TBX2 3＇UTR DNA sequencing. According to our screening results,the identified variants were chosen for genotying by SNa Pshot and association analysis in both groups. Then cell transfection and luciferase activity tests were conducted in functional analysis of the positive variant. Results A total of 768 cases were enrolled in CHD group,with mean age 6. 1 ±4. 8 years and 383 male subjects（ 49. 9%）. The control group included660 subjects,with mean age 6. 5±3. 2 years and 354 male subjects（ 53. 6%）. 1Three known SNPs in 3＇UTR were identified by DNA sequencing in our 24 CHDs and 24 controls： rs59382073,rs1058004 and rs729782. There was no novel variant. 2 The initial association study in 288 cases and 288 controls indicated that genotypes of rs59382073 distributed significantly differently between groups（ P = 0. 012）,whereas no statistic disparity was observed for the rest two SNPs（ P〈0. 05）. Therefore,the two negative SNPs were not tested in the following subjects. 3 Our all case-control analysis indicated that TBX2 3＇ UTR rs59382073 variant was significantly associated with susceptibility of sporadic CHD. CT / TT genotype was significantly assocaited with higher risk of CHD（ adjusted OR = 2. 13,95% CI： 1. 51-2. 99,P = 1. 44×10-5）,and conotruncal defects（ OR=2. 75,95% CI： 1. 57-4.81,P = 3. 99×10-4）. And in stratified analysis,this association was further confirmed in tetralogy of Fallot（ OR = 3