Elsevier

Cytokine

Volume 136, December 2020, 155285
Cytokine

Short communication
IL17RA in early-onset coronary artery disease: Total leukocyte transcript analysis and promoter polymorphism (rs4819554) association

https://doi.org/10.1016/j.cyto.2020.155285Get rights and content

Highlights

  • The IL17 pathway is important in the development of atherosclerotic plaques.

  • IL17A/17RA polymorphisms have been associated with inflammatory diseases.

  • We did not find difference between Il17 variants in coronary disease and controls.

  • The Il-17RA was significantly overexpressed in leukocytes from patients.

Abstract

Background and aims

The interleukin-17 (IL-17) pathway would play an important role in the pathogenesis of atherosclerosis and coronary-artery disease (CAD). The IL-17 inflammatory mediators are expressed by Th17 cells, a group of CD4 + leukocytes that infiltrate the vascular milieu and are pivotal in the origin, progression, stability and rupture of the atherosclerotic lesion. Cigarette smoke compounds stimulated the expression of IL-17 and IL-17-receptors. In atherogenic mice models the deficiency of IL-17RA resulted in a reduction of the atherosclerotic lesion size and leukocyte infiltrate. We hypothesised that common the IL-17RA transcript might be differential expressed in the leukocytes from CAD patients and healthy individuals.

Methods

The relative amount of the IL-17RA to ACTB transcript was determined in total leukocytes of 55 patients and 50 controls, all smokers. We genotyped the IL-17RA rs48195554 promoter polymorphisms in 390 healthy controls and 450 early-onset CAD patients.

Results

Patients showed significantly higher mean IL-17RA normalised transcript value than controls (p < 0.001). For the IL-17RA rs48195554 promoter polymorphisms, IL-17RA G-carriers showed higher transcript values. However, allele and genotype frequencies did not differ between patients and controls and we thus excluded a significant association with CAD.

Conclusions

The higher levels of the IL-17RA transcript among CAD-patients was in agreement with a role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis.

Introduction

Coronary artery disease (CAD) is mainly due to the development of atherosclerotic lesions in the coronary vessels [1]. Atherosclerosis and CAD are strongly associated with risk factors such as hypercholesterolaemia, smoking, hypertension, and diabetes. Several stimuli, such as high levels of modified low-density lipoprotein cholesterol (LDL-c), promote the vascular inflammatory process and play a major role in the development of atherosclerotic plaques [2]. Several studies have associated atherosclerosis and the immune response. For instance, an increased incidence of atherosclerotic disease has been reported among patients with psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and other immune-mediated diseases [3]. In this context, the early stage of atherosclerosis is characterised by T-cells infiltrate into the arterial intima, a hallmark of the atherosclerotic process [4].

Th17 are a group of CD4 + cells that would regulate the progression of atherosclerosis [5]. This cells secrete cytokines of the Il-17 family, that animal studies have shown to be important for the origin, progression, stability and rupture of the atherosclerotic lesion [6], [7], [8]. The inhibition of il-17a in mice reduced the vascular inflammatory burden and cellular infiltration, and prevented the progression of the atherosclerotic lesion improving the lesion stability [6]. Human carotid plaque stimulated with IL-17A showed an increased expression of pro-inflammatory markers, while the pharmacological blockade of il-17a prevented the progression of atherosclerotic lesions and induced plaque stabilization in apolipoprotein E–deficient mice [6]. In reference to the IL-17-receptors, in the atherogenic mice null for the LDL-receptor (LDLr-/-) the deficiency of the il-17 receptor A (il-17ra) resulted in a reduction of the lesion size and leukocyte infiltrate [9]. The protective effect of deleting il-17ra could be due to a reduction of the capacity of monocytes to adhere to the aortic wall, a process that is mediated by binding of il-17a cytokines to the receptor. The deletion of il-17ra would thus result in a reduction of pro-inflammatory mediators in the nascent atherosclerotic lesion [9].

Previous studies have shown that cigarette smoke extract (CSE) stimulated the expression of IL-17-receptors in peripheral blood leukocytes (PBLs) [10]. The epithelium from central and distal airways of smokers with chronic obstructive pulmonary disease (COPD) showed increased immunoreactivity for IL-17 and IL-17R [11]. These findings linked smoking with the levels of IL-17 molecules, and could also explain the association between smoking and atherosclerosis/CAD.

CAD is a multifactorial disease with both, acquired (classical) risk factors and inherited predisposition. Rare familial forms of CAD are caused by highly penetrant pathogenic variants in a few genes, but for most of the CAD cases the genetic predisposition resides in common variants (polymorphisms) in candidate genes that encode components of the vascular endothelium physiology and would thus participate in the origin and progression of the atherosclerotic lesion [12]. Based on the recognised role of inflammation in the development of atherosclerosis we can speculate that functional variants in genes that encode inflammatory proteins might be associated with the risk of CAD [13], [14]. We hypothesised that DNA variants in the IL-17RAgene could contribute to the risk of developing CAD, and to validate this hypothesis we genotyped a common single nucleotide polymorphisms (SNPs) in CAD-patients and healthy controls. In addition, we measured the level of the IL-17RA transcript in PBLs from patients and controls.

Section snippets

Study subjects

The study was approved by the Ethical Committee of Hospital Central Asturias. All the participants were Caucasians from the region of Asturias (a Northern Spain region with a total population of approximately one million) and gave their informed consent [14]. Early-onset coronary artery disease (EO-CAD) was defined as a coronary ischaemic episode at an age ≤ 55 years. >90% of the EO-CAD cases who attended our Cardiology Department were men, and for this reason our study was based on only male

IL-17RA transcript analysis

We quantified the relative amount of the IL-17RA transcript (relative to constitutively expressed ACTB) in leukocytes from 55 patients and 50 controls. The mean CT value was significantly lower in patients (p < 0.001) (supplementary table). This suggested that the IL-17RA transcript was over-expressed in the leukocytes from the patients (Fig. 1). Our study was performed on RNA from total blood leukocytes and the results would thus be representative of all the nucleated blood cells. The

Conclusions

We report significantly higher levels of the IL-17RA transcript among CAD-patients, that was in agreement with a role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis. Our study was based on a limited number of patients and would thus require validation by others, as well as the study of specific cell-subtypes. Due to the reduced atherosclerosis in mice treated with Il-17RA inhibitors, the blockade of this receptor could be effective to attenuate the progression of coronary

Contributorship

All the authors contributed to this work by recruiting the cohorts or performing the genetic and statistical analysis.

Data accessibility

An excel file containing the anthropometric and genetic data of the studied cohorts is available in the Mendeley site (http://dx.doi.org/10.17632/p5mvg6zmmn.2).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by a grant from the Spanish Plan Nacional de I + D + I Ministerio de Economía y Competitividad and the European regional development fund, grants ISCIII-Red de Investigación Renal-REDINREN RD16/0009/0005 (EC).

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