目的：应用病例-对照方法对GATA4 基因及FOG2基因上的15个单核苷酸多态性位点 (single nucleotide polymorphisms SNPs)以及单体型与先天性心脏病（CHD）之间进行关联性分析，探讨GATA4 基因及FOG2基因在房间隔缺损（ASD）及室间隔缺损（VSD）发病人群中的作用。方法：本实验研究对象共225例，其中先心病112例(房间隔缺损 19例、室间隔缺损93 例)，正常对照113例。每位患者抽取静脉血2ml，肝素抗凝。采用质谱法对GATA4 基因及FOG2基因上所选SNPs进行分型。通过Hardy-weinberg的遗传平衡检验，在对照组中对所测基因型频率进行筛选；在不同遗传模式下，对每一个SNP位点进行与先天性心脏病之间的关联性分析；进行不同SNPs标记之间的连锁不平衡分析并构建单体型；估算单体型频率，并对不同单体型进行与先心病的关联性分析。所有以上统计分析的显著性差异的P值水平为<0.05。结果：1. 位于GATA4基因的rs2898292和 rs2173117在共显性和超显性模式下，表现与房、室间隔缺损显著相关。超显性是其主要遗传模式。2.位于FOG2基因的单体型SNP9(rs13250492)/SNP10(rs13280496) 与房、室间隔缺损存在显著的相关性，是房、室间隔缺损的主要风险因素。3.位于GATA4基因的rs2898292位点的A等位基因和rs6983129的A等位基因位点，位于FOG2基因rs12549007的C等位基因和rs13250492的A等位基因在房、室间隔缺损人群中可能具有保护性意义，其主要遗传模式为超显性。4.位于FOG2基因rs7828657的A等位基因在房、室间隔缺损人群中可能具有保护性意义。其主要遗传模式为隐性。5. SNPs之间的连锁不平衡分析表明位于基因GATA4的 rs2029969和rs2173117之间，位于基因FOG2的rs13250492和rs13280496之间分别存在显著相关，并可以稳定遗传。结论：位于GATA4基因的rs2898292和rs2173117在共显性和超显性模式下，表现与房、室间隔缺损显著相关。位于FOG2基因的单体型SNP9(rs13250492)/SNP10(rs13280496) 是房、室间隔缺损人群的主要风险因素。因此，GATA4基因、 FOG2基因是房、室间隔缺损人群的主要易感基因，这为进一步阐明房间隔缺损及室间隔缺损人群的发病的分子遗传学机制提供了实验依据。关键词:先心病；GATA4； FOG2；SNP

Objective:We selected 15 single nucleotides polymorphisms (SNPs) located in the GATA4 gene and FOG2 gene. By using the case-control association analysis, we investigated the relationship between congenital heart disease (CHD) and the single SNP and haplotypes consisting of these SNPs. As a result, we tried to find out if the GATA4 gene and the FOG2 gene were the susceptibility genes of the CHD in China.Methods: 225 unrelated patients from the First Hospital of Tsinghua University were divided into experimental group and control group. Experimental group included 19 cases of Artrial Spetal Defect（ASD）and 93 cases of Ventricular Septal Defect (VSD). Blood samples were obtained from 225 cases. Genotyping was performed by the spectrometry. The deviation from Hard-Weinberg equilibrium was examined in controls. Based on the logistic regression method, the case-control association of genotypes in five inheritance models was tested for 15 single SNPs. Pairwise Linkage Disequilibium(LD) was calculated for the cases and controls in Chinese population. The haplotype blocks were constructed based on the results of LD analysis. The association of the haplotypes with CHD was similar to that of genotypes of single SNP by logistic regression. The significance of all these tests was 0.5.Results: We found that significant genetic association between rs2898292 /rs2173117 located in the GATA4 gene and ASD and VSD was observed by the model of codominant and overdominant in the experiment. The main inheritance model was overdominant. Significant genetic association between the halotype of SNP9(rs13250492)/SNP10(rs13280496) in the FOG2 gene and ASD and VSD indicated that FOG2 gene was a major genetic risk factor. The allele A of rs2898292 and the allele A of rs6983129 in the GATA4 gene were the protective factors to Chinese people, for which the overdominant was accepted as the main inheritance model. The allele C of rs12549007 and the allele A of rs13250492 in the FOG2 gene were protective factors to Chinese people, for which the overdominant was accepted as the main inheritance model. The allele A of rs7828657 in the FOG2 gene was protective to Chinese people, for which the recessive was accepted as the main inheritance model. We found strong LD between some pairs of the markers which was rs2029969 and rs2173117 located in the GATA4 gene；rs12549007 and rs2957440 located in the FOG2 gene；rs13250492 and rs13280496 located in the FOG2 gene.Conclusion: GATA4 gene and FOG2 gene were significantly associated with ASD and VSD. They are genetically predisposed to ASD and VSD. The association study between ASD and VSD and these genes provided the genetic bases of the etiology of CHD.Key words: CHD; GATA4; FOG2; SNP