Notch信号通路基因JAG1、ADAM17和ADAM10与先天性心脏病(CHD)的相关性

 目的  探索Notch通路的配体JAG1和限速酶ADAM10和ADAM17与先天性心脏病(congenital heart disease,CHD)发病的相关性。方法  选取来自山东、上海两地的1 053例CHD患者血液样本和1 000例对照样本,对这3个基因的5′启动子区和3′-UTR区进行了全测序,并进行统计分析及简要功能验证。结果  检测到7个SNP (含2个新发SNP位点Ch2:9695908T/C和Ch20:10655928T/C)和1个单倍型组合具有显著性频率差异。双荧光素酶报告基因试验表明其中ADAM17启动子区的rs3811592M rs13415726M rs3811591M这个连锁单倍型可显著下调基因表达;而JAG1启动子区的rs7264849M则可显著上调基因表达。结论  这些SNP突变可能影响Notch信号的强弱,从而与心脏发育异常相关。

Association study of Notch pathway genes JAG1,ADAM17 and ADAM10 in congenital heart diseases (CHD)

Objective  To study the relationship between Notch ligand JAG1,rate-limiting enzymes ADAM10 and ADAM17 and congenital heart disease (CHD).Methods  We sequenced those three genes′ promotor region and 3′-UTR region in 1 053 CHD cases and 1 000 controls from Shanghai and Shandong Province.Statistical analysis and brief functional verification were made.Results  We found 7 SNPs and 1 Haplotype in the non-coding region which were significantly higher in frequency in cases than in controls (P<0.0001).Dual-luciferase assay proved that the rs3811592M rs13415726M rs3811591M and haplotype in the promoter region of ADAM17 could significantly down-regulate the gene expression,while the SNP rs7264849M in the promoter region of JAG1 could significantly up-regulate the gene expression,which in turn can contribute to abnormal heart decelopment.Conclusions  These SNPs may affect the Notch pathway and results in signaling disorder.