Person:

Zhang, Xiaomin

Background: 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 greater than 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.

Background: There is ample evidence that Hsp70 takes part in the progress of coronary heart disease (CHD). This implies that genetic variants of Hsp70 genes such as HSPA8 (HSC70) gene might contribute to the development of CHD. The present study aimed to investigate whether certain genetic variants of HSPA8 gene are associated with CHD in Han Chinese people. Methodology/Principal Findings: A total of 2006 subjects (1003 CHD cases and 1003 age- and sex- matched healthy controls) were recruited. Genetic variants in the HSPA8 gene were identified by sequencing of the gene in 60 unrelated Chinese. Four tag single nucleotide polymorphisms (tagSNPs) (rs2236659, rs2276077, rs10892958, and rs1461496) were selected and genotyped. The function of the significant SNP was evaluated using luciferase reporter assays in two cell lines. By sequencing the promoter and all exons and introns of the HSPA8 gene, 23 genetic variants were identified. One promoter SNP rs2236659 was associated with susceptibility to CHD. Carriers of the “C” allele of rs2236659 had decreased CHD risk with odds ratio (OR) of 0.78 (95% CI: 0.62, 0.98; P = 0.033) after adjustment for conventional risk factors. Haplotype analyses indicated that haplotype GCGC contributed to a lower CHD risk (OR = 0.78, 95% CI: 0.65, 0.93; P = 0.006) compared with the common haplotype AGGT. In a transfection assay, the C allele of rs2236659 showed a 37–40% increase in luciferase expression of the reporter gene luciferase in endothelial and non-endothelial cells compared with the T allele. Conclusions/Significance: These findings suggest that genetic variants in HSPA8 gene (especially promoter SNP rs2236659) contribute to the CHD susceptibility by affecting its expression level.