易感基因多态性与孕期环境因素对先天性心脏病风险的交互作用分析
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摘要
目的分析先天性心脏病中TBX5基因、MTHFR基因与环境因素的交互作用。方法回顾性分析2012年12月至2015年5月山东大学齐鲁儿童医院就诊的单纯先天性心脏病患儿150例。应用单因素和多因素非条件logistic回归模型分析环境因素与先天性心脏病的关系并计算OR(95%CI),利用多因子降维法(MDR)进行交互作用分析。结果妊娠高血压综合征和孕期情绪状态是先天性心脏病可能的环境危险因素,基因-基因交互作用MDR模型筛选中,1阶与2阶交互作用最佳预测模型交叉验证一致性均不高,基因-环境交互作用MDR模型筛选中,最优交互模型是孕母情绪状态、MTHFR基因rs1801133位点多态与TBX5基因rs883079位点多态,该模型的拟合均衡准确性为0.685,检测均衡准确性为0.613,交叉验证一致性为10/10。TBX5基因rs883079、MTHFR基因rs1801133和rs1801131位点可能与先天性心脏病存在关联,MTHFR和TBX5基因可能存在交互作用,但交互作用不明显。结论孕母情绪状态MTHFR基因和TBX5基因在先天性心脏病中具有显著交互效应,可增加先天性心脏病的发病风险。
Objective To elucidate the interaction between TBX5 gene, MTHFR gene and environmental factors in congenital heart disease(CHD). Methods A retrospective case-control study was conducted in which 150 CHD cases and 150 controls were included from December 2012 to May 2015 in Qilu Children′s Hospital of Shandong University. Single factor and multiple factors unconditional logistic regression models were used to analyze the correlation between environmental factors during pregnancy and CHD, and to calculate the odds ratio and 95% confidence interval. Multifactor dimensionality reduction(MDR) was used for interaction analysis. Results Gestational hypertension syndrome and emotional change were possible environmental risk factors for CHD.In the screening of the gene-gene interaction MDR model, the cross-validation consistency of the best prediction model with the interaction of order 1 and order 2 was not high, while in the screening of the gene-environment interaction MDR model, the optimal interaction model was found to be the maternal emotional change, the polymorphism of MTHFR rs1801133 and the polymorphism of TBX5 rs883079. The model′s fitting and equalization accuracy was 0.685, the testing equalization accuracy was 0.613, and the cross validation consistency was 10/10.The TBX5 gene rs883079, MTHFR gene rs1801133 and rs1801131 may be associated with CHD. Conclusions Maternal emotion,MTHFRgene and TBX5 gene may have interaction in CHD,which can increase the risk of CHD.
Objective To elucidate the interaction between TBX5 gene, MTHFR gene and environmental factors in congenital heart disease(CHD). Methods A retrospective case-control study was conducted in which 150 CHD cases and 150 controls were included from December 2012 to May 2015 in Qilu Children′s Hospital of Shandong University. Single factor and multiple factors unconditional logistic regression models were used to analyze the correlation between environmental factors during pregnancy and CHD, and to calculate the odds ratio and 95% confidence interval. Multifactor dimensionality reduction(MDR) was used for interaction analysis. Results Gestational hypertension syndrome and emotional change were possible environmental risk factors for CHD.In the screening of the gene-gene interaction MDR model, the cross-validation consistency of the best prediction model with the interaction of order 1 and order 2 was not high, while in the screening of the gene-environment interaction MDR model, the optimal interaction model was found to be the maternal emotional change, the polymorphism of MTHFR rs1801133 and the polymorphism of TBX5 rs883079. The model′s fitting and equalization accuracy was 0.685, the testing equalization accuracy was 0.613, and the cross validation consistency was 10/10.The TBX5 gene rs883079, MTHFR gene rs1801133 and rs1801131 may be associated with CHD. Conclusions Maternal emotion,MTHFRgene and TBX5 gene may have interaction in CHD,which can increase the risk of CHD.
引文
[1] 邓木兰,梁巧容,陈寄梅,等.简单先天性心脏病患者疾病经济负担影响因素分析[J].岭南心血管病杂志,2018,24(2):210-216.
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[10] Vecoli C, Pulignani S, Foffa I, et al.Congenital heart disease:the crossroads of genetics, epigenetics and environment[J].Curr Genomics, 2014, 15(5):390-399.
[11] Hobbs CA, Cleves MA, Karim MA, et al.Maternal folate-related gene environment interactions and congenital heart defects[J].Obstet Gynecol, 2010, 116(2 Pt 1):316-322.
[12] 蒋幼芳, 梅瑾, 张闻,等.围孕期妇女营养摄入与胎儿先天性心脏病的关系[J].国际流行病学传染病学杂志, 2015, 42(5):320-324.
[13] Hobbs CA, James SJ, Jernigan S, et al.Congenital heart defects, maternal homocysteine, smoking, and the 677 C>T polymorphism in the methylenetetrahydroflate reductase gene:Evaluating gene-environment interactions[J].Am J Obstet Gynecol, 2006, 194(1):218-224.
[14] Wang L, Yang B, Zhou S, et al.Risk factors and methylenetetrahydrofolate reductase gene in congenital heart disease[J].J Thorac Dis, 2018, 10(1):441-447.
[15] Maitra M, Schluterman MK, Nichols HA, et al.Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development[J].Dev Biol, 2009, 326(2):368-377.
[2] 李河, 庄建, 石美玲, 等.先天性心脏病患儿手术治疗直接经济负担分析[J].中国卫生经济, 2011, 30(3):42-44.
[3] Zhu T, Qiao L, Wang Q, et al.T-box family of transcription factor-TBX5, insights in development and disease[J].Am J Transl Res, 2017, 9(2):442-453.
[4] Wang L, Yang B, Zhou S, et al.Risk factors and methylenetetrahydrofolate reductase gene in congenital heart disease[J].J Thorac Dis, 2018, 10(1):441-447.
[5] Li D, Yu K, Ma Y, et al.Correlationship between congenital heart disease and polymorphism of MTHFR gene[J].J Hygiene Res, 2015, 44(6):933-938.
[6] Wang Y, Zhang H, Yue S, et al.Evaluation of high resolution melting for MTHFR C677T genotyping in congenital heart disease[J].PLoS One, 2016, 11(3):e0151140.
[7] Wang F, Liu D, Zhang RR, et al.A TBX5 3′UTR variant increases the risk of congenital heart disease in the Han Chinese population[J].Cell Discov, 2017, 3:17026.
[8] Steimle JD, Moskowitz IP.TBX5:A key regulator of heart development[J].Curr Top Dev Biol, 2017, 122:195-221.
[9] Sinner MF, Tucker NR, Lunetta KL, et al.Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation[J].Circulation, 2014, 130(15):1225-1235.
[10] Vecoli C, Pulignani S, Foffa I, et al.Congenital heart disease:the crossroads of genetics, epigenetics and environment[J].Curr Genomics, 2014, 15(5):390-399.
[11] Hobbs CA, Cleves MA, Karim MA, et al.Maternal folate-related gene environment interactions and congenital heart defects[J].Obstet Gynecol, 2010, 116(2 Pt 1):316-322.
[12] 蒋幼芳, 梅瑾, 张闻,等.围孕期妇女营养摄入与胎儿先天性心脏病的关系[J].国际流行病学传染病学杂志, 2015, 42(5):320-324.
[13] Hobbs CA, James SJ, Jernigan S, et al.Congenital heart defects, maternal homocysteine, smoking, and the 677 C>T polymorphism in the methylenetetrahydroflate reductase gene:Evaluating gene-environment interactions[J].Am J Obstet Gynecol, 2006, 194(1):218-224.
[14] Wang L, Yang B, Zhou S, et al.Risk factors and methylenetetrahydrofolate reductase gene in congenital heart disease[J].J Thorac Dis, 2018, 10(1):441-447.
[15] Maitra M, Schluterman MK, Nichols HA, et al.Interaction of Gata4 and Gata6 with Tbx5 is critical for normal cardiac development[J].Dev Biol, 2009, 326(2):368-377.
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