EDNRA affects susceptibility to large artery atherosclerosis stroke through potential inflammatory pathway

Abstract

This study aimed to explore the potential association between Endothelin type A receptor (EDNRA) genetic polymorphisms and susceptibility to large artery atherosclerotic stroke (LAA), as well as the involvement of inflammation mechanisms. We recruited Han Chinese patients with LAA and age- and sex-matched controls. The distribution of alleles and genotypes for 16 single nucleotide polymorphisms (SNPs) in EDNRA was analyzed using dominant, recessive, and co-dominant genetic models between cases and controls. We quantified the mRNA and protein levels of EDNRA and NLRP3 genes, and concentrations of inflammatory factors (TNFα, IL-1β, IL-6, IL-8, IL-10, IL-18, and CCL18) in peripheral blood samples randomly selected from cases and controls. We also investigated the relationship between these SNPs, gene expression patterns and inflammatory factor levels. A total of 428 LAA cases and 434 controls were enrolled in this study. The results showed that rs5343 TT genotype of EDNRA was significantly associated with an increased risk of LAA (OR = 3.243, 95%CI = 1.608-6.542, P = 0.001). It also demonstrated a significant upregulation level of NLRP3 as well as higher concentrations of IL-10, IL-18, and CCL-18 in cases compared to controls. Besides, we discovered that the EDNRA polymorphisms were linked to NLRP3, IL-6, IL-10, and IL-18 levels in cases. There existed a positive correlation between EDNRA transcription levels and both NLRP3 transcript levels (r = 0.437, p < 0.001) and IL-18 concentrations (r = 0.212, p < 0.001). EDNRA is linked to susceptibility of LAA. This association may be attributed to the NLRP3-mediated inflammatory pathway.

Keywords: EDNRA; Inflammation; Interaction; Large artery atherosclerotic stroke; SNP.

Fig. 1

LD and correlation coefficients (r²) among sixteen selected SNPs of the EDNRA gene.

Fig. 2

Risk of 9 different combinations of rs2048894 and rs5343 genotypes. High-risk cells are indicated by dark color, low-risk cells are indicated by light color. The high-risk interaction genotype was assigned as one, and low-risk interaction genotype was assigned as zero in multivariable logistic regression analysis.

Fig. 3

Levels of inflammation-related factors in the control group and LAA group. Outlier detection was conducted using the 3-sigma criterion. Values are shown as means ± SEM, ^*p < 0.05, ^****p < 0.0001.

Fig. 4

EDNRA polymorphism is associated with inflammation in LAA patients. No significant differences were observed in the levels of inflammatory factors at the relevant polymorphic loci in the control group. Values are shown as means ± SEM, ^*p < 0.05, ^**p < 0.01.

Fig. 5

EDNRA expression is positively correlated with NLRP3 expression and IL18 levels in LAA patients.