GATA5基因启动子序列单核苷酸多态性可增加急性心肌梗死的易感性

Single nucleotide polymorphisms in promoter sequence of GATA5 gene increase susceptibility to acute myocardial infarction

目的:通过病例-对照研究,探讨GATA结合蛋白5(GATA binding protein 5,GATA5)基因启动子序列单核苷酸多态性(single nucleotide polymorphism,SNP)与急性心肌梗死(acute myocardial infarction,AMI)的相关性。方法:通过χ~2检验、logistic回归、单倍型分析、细胞转染及电泳迁移率变动分析(electrophoretic mobility shift assay,EMSA)对SNPs进行遗传及功能分析。结果:校正混杂因素后,rs80197101位点GA和GA+AA基因型与AMI显著相关(OR=2.280,95%CI:1.027~5.061,P=0.043;OR=2.312,95%CI:1.045~5.116,P=0.039)。rs77067995位点CT和CT+TT基因型也与AMI显著相关(OR=2.280,95%CI:1.027~5.061,P=0.043;OR=2.312,95%CI:1.045~5.116,P=0.039)。rs80197101和rs77067995呈完美连锁不平衡,两者形成的单倍型AT在AMI组的频率显著高于对照组(χ~2=6.960,P=0.008)。EMSA及转染结果表明,这些SNPs通过影响转录因子与GATA5基因启动子的结合,显著增加GATA5基因启动子在HEK-293细胞和H9c2细胞中的转录活性(P<0.001)。结论:GATA5基因启动子序列中的rs80197101与rs77067995可显著增加AMI的易感性。rs80197101的等位基因A和rs77067995的等位基因T可能是AMI的危险等位基因,单倍型AT可能是AMI的危险单倍型。

AIM: To investigate the relationship between single nucleotide polymorphisms(SNPs) of GATA binding protein 5(GATA5) gene promoter sequence and acute myocardial infarction(AMI) by case-control study. METHODS: The SNPs of GATA5 gene promoter were analyzed by Chi-square test, logistic regression analysis, haplotype analysis, cell transfection and electrophoretic mobility shift assay(EMSA). RESULTS: After adjusting for confounding factors, GA and GA+AA genotypes of rs80197101 were correlated with AMI(OR=2.280, 95% CI: 1.027~5.061, P=0.043;OR=2.312, 95% CI: 1.045~5.116, P=0.039). CT and CT+TT genotypes of rs77067995 were also correlated with AMI(OR=2.280, 95% CI: 1.027~5.061, P=0.043;OR=2.312, 95% CI: 1.045~5.116, P=0.039). rs80197101 and rs77067995 showed perfect linkage disequilibrium, and the frequency of haplotype AT in AMI group was significantly higher than that in control group(χ~2=6.960, P=0.008). The results of EMSA and transfection experiments showed that these SNPs may increase the transcriptional activity of GATA5 gene promoter by interfering with the binding of KLF6 and SMAD transcription factors to GATA5 gene promoter, and then alter the expression of GATA5 gene, thus increasing the susceptibility to AMI. CONCLUSION: The SNPs [g.62476317 G>A(rs80197101) and g.62476223 C>T(rs77067995)] of GATA5 gene promoter increase the susceptibility to AMI. The genotype GA of rs80197101 and the genotype CT of rs77067995 may be the risk genotypes of AMI. The allele A of rs80197101 and the allele T of rs77067995 may be the risk alleles of AMI, and the haplotype AT may be the risk haplotype of AMI.