He Meian, Guo Huan, Yang Xiaobo, Zhang Xiaomin, Zhou Li, Cheng Longxian, Zeng Hesong, Hu Frank B, Tanguay Robert M, Wu Tangchun
Institute of Occupational Medicine and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
PLoS One. 2009;4(3):e4851. doi: 10.1371/journal.pone.0004851. Epub 2009 Mar 31.
HSP70 plays crucial roles in endothelial cell apoptosis, which is involved in the early phase and progress of coronary heart disease (CHD). However, the association between polymorphisms of HSP70 genes and the risk of CHD still remains unclear. Our aim was to determine whether genetic variants in the HSPA1A gene are associated with the risk of CHD.
METHODOLOGY/PRINCIPAL FINDINGS: By resequencing and genotyping, the associations of 2 single nucleotide polymorphisms (SNPs) +190G/C (rs1043618) and -110A/C (rs1008438) in the HSPA1A gene with risk of CHD were determined in a 1,003 pairs case-control study. The SNP function was further analyzed using a luciferase reporter assay in two cell lines. The results indicated that +190CC genotype was associated with significantly higher risk of CHD when compared with +190GG genotype (OR = 1.56, 95% CI: 1.10-2.20, P = 0.012), while association between -110A/C polymorphism and CHD was not statistically significant (P>0.05). However, the -110C/+190C haplotype had a significantly higher risk of CHD when compared with the -110A/+190G haplotype (OR = 1.17, 95% CI: 1.01-1.34, P = 0.031). Luciferase reporter assays showed that the +190C allele resulted in 14% ~ 45% reduction in luciferase expression in endothelial and non-endothelial cells when compared with the +190G allele.
CONCLUSIONS/SIGNIFICANCE: The identified genetic variants in the HSPA1A gene combinatorially contribute towards the susceptibility to CHD likely by affecting the level of synthesis of HSP70. This study may provide useful markers for identification of subjects at risk for CHD.
热休克蛋白70（HSP70）在内皮细胞凋亡中起关键作用，而内皮细胞凋亡参与冠心病（CHD）的早期阶段和进展。然而，HSP70基因多态性与冠心病风险之间的关联仍不清楚。我们的目的是确定热休克蛋白家族A成员1A（HSPA1A）基因中的遗传变异是否与冠心病风险相关。
方法/主要发现：通过重测序和基因分型，在一项包含1003对病例对照的研究中，确定了HSPA1A基因中的两个单核苷酸多态性（SNP）+190G/C（rs1043618）和 -110A/C（rs1008438）与冠心病风险的关联。使用荧光素酶报告基因检测在两种细胞系中进一步分析了SNP功能。结果表明，与+190GG基因型相比，+190CC基因型与冠心病风险显著更高相关（比值比[OR]=1.56，95%置信区间[CI]：1.10 - 2.20，P = 0.012），而 -110A/C多态性与冠心病之间的关联无统计学意义（P>0.05）。然而，与 -110A/+190G单倍型相比，-110C/+190C单倍型具有显著更高的冠心病风险（OR = 1.17，95% CI：1.01 - 1.34，P = 0.031）。荧光素酶报告基因检测显示，与+190G等位基因相比，+190C等位基因导致内皮细胞和非内皮细胞中荧光素酶表达降低14%至45%。
结论/意义：在HSPA1A基因中鉴定出的遗传变异可能通过影响HSP70的合成水平，共同导致对冠心病的易感性。本研究可能为识别冠心病风险个体提供有用的标志物。
