[SIRT1基因启动子区域单核苷酸多态性与老年退行性心脏瓣膜病的关系]

[Association between single nucleotide polymorphism in promoter region of SIRT1 gene and senile degenerative heart valvular disease].

作者信息

Song Z P, Li J R, Gao R, Cui Y H, Pang S C, Yan B

机构信息

Department of Medicine, Shandong University School of Medicine, Jinan 250014, China.

Department of Cardiology, Affiliated Hospital of Jining Medical University, Jining 272000, China.

出版信息

Zhonghua Yi Xue Za Zhi. 2020 Apr 7;100(13):991-996. doi: 10.3760/cma.j.cn112137-20190716-01575.

DOI:10.3760/cma.j.cn112137-20190716-01575

PMID:32294855

Abstract

To investigate the correlation between single nucleotide polymorphisms (SNPs) of SIRT1 gene promoter sequence and senile degenerative heart valvular disease (SDHVD). A total of 236 SDHVD patients and 285 healthy controls who visited the Affiliated Hospital of Jining Medical University between February 2012 and October 2016 were enrolled. SNPs of SIRT1 gene promoter were detected by Sanger sequencing. Typing and correlation were analyzed by χ(2) test and Logistic regression analysis. Haplotype and linkage disequilibrium were analyzed by Haploview4.2 software and SHEsis online software. The effect of SNPs on the binding of transcription factors to SIRT1 gene promoter was analyzed by electrophoretic mobility shift assay(EMSA). The transcription factors affected by SNPs were predicted by Transfac online software. The frequency distribution of GG genotype of rs3740051 in the SDHVD group was significantly higher than that in the control group (χ(2)=4.855, 0.028). There was a correlation between GG genotype of the rs3740051 and SDHVD. After adjusting for age, the risk of SDHVD in the carrier of GG genotype was 3.079 times higher than that of AA genotype(3.079, 95: 1.156-8.201, 0.024). The five SNPs (rs3740051, rs932658, rs35995735, rs3740053 and rs2394443) showed strong linkage disequilibrium(D'>0.8). The haplotype analysis of the five SNPs (haplotype frequency<0 was ignored in the analysis) showed that 11 haplotypes (0.05) were formed, and the frequency of AC, AAC, AGC, AAGC, AA*AC, *AGAC and AAGAC in SDHVD group were significantly higher than that in control group (0.05, 1, 95 does not contains 1). EMSA showed that the color of the binding bands incubated by wild type probe and nucleoprotein was darker than that incubated by DNA sequence variation probe and nucleoprotein. The GG genotype of rs3740051 is associated with SDHVD and may be a risk genotype for SDHVD. The haplotype AC (across rs932658 and rs2394443) may be a dangerous haplotype of SDHVD. rs3740051 may affect the occurrence and development of SDHVD by interfering with the binding of FOXC protein to SIRT1 gene promoter.

摘要

探讨沉默信息调节因子1（SIRT1）基因启动子序列单核苷酸多态性（SNP）与老年退行性心脏瓣膜病（SDHVD）的相关性。选取2012年2月至2016年10月在济宁医学院附属医院就诊的236例SDHVD患者和285例健康对照者。采用桑格测序法检测SIRT1基因启动子的SNP。通过χ²检验和Logistic回归分析进行分型及相关性分析。利用Haploview4.2软件和SHEsis在线软件进行单倍型及连锁不平衡分析。采用电泳迁移率变动分析（EMSA）检测SNP对转录因子与SIRT1基因启动子结合的影响。通过Transfac在线软件预测受SNP影响的转录因子。SDHVD组rs3740051的GG基因型频率分布显著高于对照组（χ² = 4.855，P = 0.028）。rs3740051的GG基因型与SDHVD存在相关性。校正年龄后，GG基因型携带者患SDHVD的风险是AA基因型的3.079倍（3.079，95%CI：1.156 - 8.201，P = 0.024）。5个SNP（rs3740051、rs932658、rs35995735、rs3740053和rs2394443）表现出强连锁不平衡（D'>0.8）。对这5个SNP进行单倍型分析（分析中忽略单倍型频率<0.05的情况），共形成11种单倍型，SDHVD组中AC、AAC、AGC、AAGC、AA*AC、*AGAC和AAGAC的频率显著高于对照组（P<0.05）。EMSA结果显示，野生型探针与核蛋白孵育后的结合带颜色比DNA序列变异探针与核蛋白孵育后的深。rs3740051的GG基因型与SDHVD相关，可能是SDHVD的风险基因型。单倍型AC（跨越rs932658和rs2394443）可能是SDHVD的危险单倍型。rs3740051可能通过干扰FOXC蛋白与SIRT1基因启动子的结合影响SDHVD的发生发展。