Xie Jun, Yi Long, Xu Zheng-Feng, Mo Xu-Ming, Hu Ya-Li, Wang Dong-Jin, Ren Hao-Zhen, Han Bing, Wang Yong, Yang Chi, Zhao Ye-Lin, Shi Dong-Quan, Jiang Yong-Zhong, Shen Li, Qiao Di, Chen Shi-Lin, Yu Bao-Jun
Department of Pathology, Nanjing University Medical School, Nanjing, People's Republic of China.
Eur J Hum Genet. 2007 Dec;15(12):1246-51. doi: 10.1038/sj.ejhg.5201890. Epub 2007 Jul 11.
The ventricular septal defect (VSD) is the most common congenital heart defect and no candidate susceptibility gene has been identified. Endocardial cushion and outflow septal morphogenesis, malalignment of which induces VSD, have been suggested to be mediated by the vascular endothelial growth factor (VEGF). Three single-nucleotide polymorphism (SNP) variants in promoter and 5'-UTR region of the VEGF gene, C-2578A (rs699947), G-1154A (rs1570360) and G-634C (rs2010963), were reported to alter its expression. We assessed the association in a Chinese population between these SNPs and VSD using a double approach: case-control and TDT designs. Among the three SNPs, only -634C allele was less frequently present in 222 patients compared to 352 controls (odds ratio: 0.76, 95% CI: 0.59-0.97, X(2)=5.06, P=0.024, not significant after a Bonferroni correction). This was significantly less transmitted to VSD patients (trios: 142) (odds ratio: 0.39, 95% CI: 0.25-0.62, X(2)=8.11, df=1, P=0.004, corrected P=0.024). A similar result was observed for haplotype -2578C/-1154G/-634C allele in both studies (in TDT: X(2)=7.51, df=1, P=0.006, corrected P=0.048). All these associations for the first time demonstrated that -634C allele was in a significant protective association against VSD, suggesting that VEGF dysregulation was involved in the pathological processes of VSD.
室间隔缺损（VSD）是最常见的先天性心脏病，目前尚未确定相关的候选易感基因。心内膜垫和流出道间隔的形态发生异常会导致VSD，而这一过程被认为是由血管内皮生长因子（VEGF）介导的。据报道，VEGF基因启动子和5'-UTR区域的三个单核苷酸多态性（SNP）变体，即C-2578A（rs699947）、G-1154A（rs1570360）和G-634C（rs2010963），会改变其表达。我们采用病例对照和传递不平衡检验（TDT）两种方法，评估了中国人群中这些SNP与VSD之间的关联。在这三个SNP中，与352名对照相比，222名患者中-634C等位基因的出现频率较低（优势比：0.76，95%可信区间：0.59-0.97，X²=5.06，P=0.024，经Bonferroni校正后无统计学意义）。该等位基因传递给VSD患者（三联体：142个）的频率显著更低（优势比：0.39，95%可信区间：0.25-0.62，X²=8.11，自由度=1，P=0.004，校正后P=0.024）。在两项研究中，对于单倍型-2578C/-1154G/-634C等位基因也观察到了类似结果（在TDT中：X²=7.51，自由度=1，P=0.006，校正后P=0.048）。所有这些关联首次表明，-634C等位基因与VSD存在显著的保护关联，提示VEGF失调参与了VSD的病理过程。
