Abstract

BACKGROUND: Human endothelin-1 (ET-1) gene polymorphism is closely associated with coronary artery disease (CAD). This study aimed to investigate the association of 2 single-nucleotide polymorphisms (SNPs), +138 I/D and Lys198Asn) of the ET-1 gene,with early onset of CAD in Han Chinese patients. We investigated the effects of Lys198Asn polymorphism on ET-1 protein expression upon stimulation with pro-inflammatory factors.

MATERIAL AND METHODS: Genotyping of the 2 SNPs +138 I/D and Lys198Asn was performed in 88 early-onset CAD patients (≤55 years for males; ≤60 years for females) and 52 healthy control participants using a polymerase chain reaction direct sequencing method. The association of the 2 SNPs was analyzed with SPSS 17.0 software. Western blotting was performed to assess the effects of ET-1 polymorphisms on ET-1 protein expression upon tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and lipopolysaccharide (LPS) stimulation in HEK-293T cells.

RESULTS: Fisher’s exact test showed that the T allele (odds ratio [OR]=3.38, P=0.02) and GT/TT genotype (OR=3.76, P=0.02) of the ET-1 gene Lys198Asn were associated with increased early-onset CAD risk. Multivariate logistic regression analysis showed smoking was the single independent variable related to early-onset CAD (P<0.05). An increase of ET-1 protein levels in cells transfected with Asn198 plasmid was seen upon TNF-α or IL-6 stimulation.

CONCLUSIONS: T allele frequency in Lys198Asn loci might be associated with the pathogenesis of early-onset CAD. T-variant might contribute to early-onset CAD by upregulating ET-1 expression upon inflammatory cytokines stimulation, and smokers who have the T allele might be vulnerable to CAD in the Chinese population.

Keywords: Coronary Artery Disease, Cytokines, Endothelin-1, Polymorphism, Single Nucleotide, Adult, Aged, Asians, Case-Control Studies, China, ethnicity, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Male, Middle Aged, Odds Ratio, Risk Factors