Association study of a functional variant of TNF-alpha gene and serum TNF-alpha level with the susceptibility of congenital heart disease in a Chinese population

摘要

Background Congenital heart disease (CHD) is among the leading causes of infant death worldwide. Although shortage of folate has been found potentially to contribute to CHD in the embryo, the aetiology of CHD was not completely understood. Inflammation and altered immune processes are involved in all forms of cardiac malformation, including CHD. Tumour necrosis factor-alpha (TNF-alpha), was involved in the pathogenesis of multiple kinds of heart diseases. However, no studies have systematically evaluated the associations of genetic variants of TNF-alpha with susceptibility of CHD. Methods A case-control study was conducted to evaluate the associations between tagSNPs of TNF-alpha and CHD susceptibility. Serum level of TNF-alpha was assessed using ELISA. The dual luciferase reporter assay was used to evaluate the functional significance of variant rs1800629 on TNF-alpha transcriptional activity. Results We found rs1800629 was significantly correlated with increased CHD susceptibility (OR: 1.72, 95% CI 1.26 to 2.36, p=0.001). Serum levels of TNF-alpha were significantly higher in CHD group (9.09 +/- 1.90 pg/mL) than that in control group (6.12 +/- 1.56 pg/mL, p<0.001). The AA genotype and AG genotype of rs1800629 was associated with higher serum TNF-alpha level, compared with GG genotype. The dual luciferase reporter assay showed that promoter activity was significantly increased by 57% and 76% for plasmids containing the minor A allele compared with the major G allele in H9c2 and HEK 293T, respectively. Conclusion These results indicate that higher level of serum TNF-alpha increases risk of CHD, while TNF-alpha rs1800629 A allele might contribute to higher risk for CHD due to the increase in TNF-alpha expression.