Interleukin-17A gene variants and risk of coronary artery disease: A large angiography-based study
Introduction
Coronary artery disease (CAD) is one of the leading causes death and loss of disability-adjusted life years in both developed and developing countries [1]. The pathogenesis of coronary atherosclerosis involves inherited, behavioral and environmental factors [1], [2]. The inflammation appears to be involved in all stages of atherosclerotic developments, including oxidative damage, cell proliferation and plaque evolution and destabilization [3], [4], [5], [6]. It has been identified that a multitude of inflammatory markers are potentially involved in orchestration of atherogenesis [7], [8], [9]. Interleukins are considered to be key players in chronic vascular inflammatory response that is typical of atherosclerosis [10], [11], [12].
In recent years, increasing evidence has emerged from experimental and epidemiological data that IL-17A, a proinflammatory cytokine involved in both innate and acquired immune responses, plays a key role in the inflammatory response that contributes to atherosclerosis [13], [14], [15]. A recent study has showed that IL-17A has potent actions to mobilize, recruit, and activate macrophages in atherosclerotic lesions. Increased IL-17A expression has been localized in human atherosclerotic plaque and associated with plaque instability as well as the beneficial effect of inhibiting IL-17A on plaque progression and composition [14], [15]. Blocking IL-17A leads to a reduction in early atherosclerotic lesion area/fractional stenosis/maximum stenosis by 50% in apoE−/− mice, a validated mouse model of atherosclerosis [16]. IL-17A may participate in the inflammatory process in plaque destabilization and circulating IL-17A levels were strongly predictive for acute coronary syndrome (ACS) [17]. By inducing the production of multiple cytokines, chemokines, and adhesion molecules in atherogenic cells, IL-17A might directly govern mononuclear cell accumulation and cell death within the plaque, which are important determinants for early atherogenesis, atherosclerotic plaque disruption and thrombosis [16]. At present experimental and clinical findings support the role of IL-17A in enhancing CAD risk, but information at a population-based genetic level is limited.
A two-stage design, including sequencing based polymorphism analysis and subsequent case–control association study, was adopted in present study to explore the possible involvement of IL17A in CAD in a Han Chinese population.
Section snippets
Subjects
A total of 1031 patients with CAD (612 males and 419 females, mean age 55.9 ± 10.1 years) and 935 control subjects (524 males and 411 females, mean age 55.2 ± 10.5 years) were included (Table 1). Patients and controls were unrelated individuals of Han Chinese from northeast region of China. All subjects had undergone standardized coronary angiography in Department of Cardiology, Shenyang Northern Hospital and were enrolled from May 2006 to November 2009. Coronary angiography was performed by
General characteristics
The main baseline characteristics of patients with CAD and controls were shown in Table 1. Controls and CAD patients were matched by age and sex. Briefly, compared to the control subjects, the male CAD group had more patients with hypertension, diabetes, and had a larger average BMI. The CAD group also had significantly higher total TC, TG and HDL-C levels than the control group. No significant difference was noted in plasma concentration LDL-C between the CAD and control group.
Description of the Polymorphisms
We performed
Discussion
Atherosclerosis, CAD and its complications, the leading cause of death and disability worldwide, are recognized as an inflammatory disease [1], [2], [3], [4]. IL-17A is a cytokine produced by Th lymphocytes cells and plays important roles in development of inflammatory diseases [17], [22]. We hypothesized that the cytokines may affect the development of CAD inflammation followed by the plasma level of proinflammatory and neutrophil-mobilizing cytokines. Thus the association of IL-17A gene and
Acknowledgments
The study was supported by a grant from the Military Medical Science and Technique Foundation during the 11th 5-Year Plan Period (No. 06G021) and State Key Development Program of Basic Research China (2009CB521900). The authors would like to thank all subjects for participating in this study and the clinical doctors for their excellent collection of samples.
References (31)
- et al.
Diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary tree: a histopathologic study of patients dying of acute myocardial infarction
J Am Coll Cardiol
(2005) - et al.
Interleukin-17 family members and inflammation
Immunity
(2004) - et al.
Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation
J Biol Chem
(2007) - et al.
Interleukin 17: an unlikely marker of acute coronary syndrome?
Atherosclerosis
(2009) - et al.
Interleukin-17 regulates chemokine and gelatinase B expression in fibroblasts to recruit both neutrophils and monocytes
Immunobiology
(2009) - et al.
Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells
Immunol Lett
(2005) Atherosclerosis—an inflammatory disease
N Engl J Med
(1999)- et al.
Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease
N Engl J Med
(2000) - et al.
The inflammatory response in myocardial infarction
Cardiovasc Res
(2002) - et al.
Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics
Circulation
(1995)
Role of inflammation in coronary plaque disruption
Circulation
Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin-6 and serum amyloid A but decreased C-reactive protein
Circulation
Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association
Circulation
Biomarkers, atherosclerosis and cardiovascular events
Expert Rev Cardiovasc Ther
Interleukins in atherosclerosis: molecular pathways and therapeutic potential
Pharmacol Rev
Cited by (0)
- 1
These authors contributed equally to this work.