Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction
Introduction
The major contribution of inflammatory mechanisms to atherosclerosis has recently been emphasized [1], [2], [3], [4]. The pattern and magnitude of cytokine release at the site of tissue injury is considered to be a critical determinant of severity and duration of the response. Interleukin-10 (IL-10) and tumor necrosis factor alpha (TNF-α) have complex and predominantly opposing roles in inflammation [1], [2], [5], [6], [7], [8], [9]. An autoregulatory loop appears to exist in which TNF-α stimulates IL-10 production, which, in turn, reduces TNF-α synthesis [10].
Playing a major role in suppressing immune and inflammatory responses, several functions of IL-10 are centered on inhibition of macrophage function, including cytotoxic activity and cytokine synthesis. In experiments with cultured cells and mice, IL-10 was found to block atherosclerotic events and it was suggested that IL-10 may arrest and reverse the chronic inflammatory response in established atherosclerosis, as well as limit thrombotic complications [11], [12].
TNF-α is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases [13]. The presence of TNF-α in the majority of atherosclerotic lesions and absence from normal tissues suggests its involvement in atherogenesis [14], [15]. TNF-α may contribute to atherosclerosis by activation of growth factors, cytokines, and chemoattractants and by effecting the synthesis and stimulation of adhesion molecules [16], [17]. Secretion of TNF-α from mononuclear leukocytes of patients with stable and unstable angina pectoris is elevated when compared with control individuals [18]. In addition, TNF-α possibly increases the risk of thrombotic events by stimulation of procoagulant activity and suppression of antithrombotic pathways in endothelial cells [19].
The human IL-10 gene is located on chromosome 1 and has been mapped to the junction between 1q31 and 1q32 [20], [21]. The genes for TNF-α and TNF-β are situated close to each other within the human leukocyte antigen (HLA) class III gene cluster on the short arm of chromosome 6, approximately 220 kilo base pairs (kbp) centromeric of the HLA-B locus and about 850 kbp telomeric of the HLA class II region [22]. Stimulation of human blood samples with bacterial lipopolysaccharide showed large interindividual variations of IL-10 and TNF-α production, suggesting a genetic component of approximately 75 and 60%, respectively [23]. Interindividual differences in the regulation of IL-10 and TNF-α production may be critical in a variety of healthy and abnormal inflammatory responses.
Several polymorphisms located close to or within the IL-10, TNF-α, and TNF-β genes are potentially associated with transcription levels, however, the molecular mechanisms linking these polymorphisms to gene expression and posttranscriptional processing are only partially known [9], [13], [24], [25], [26], [27], [28], [29], [30], [31], [32]. The best documented of these polymorphisms are the IL-10 gene promoter polymorphisms −1082G/A, −819C/T, and −592C/A, the TNF-α promoter polymorphisms −863C/A and −308G/A, as well as the TNF-β intron 1 polymorphism 252G/A [28], [33], [34], [35], [36], [37].
This study was based on the assumption that the IL-10 and TNF gene polymorphisms have a measurable influence on atherosclerotic mechanisms and contribute to or reduce the occurrence of coronary artery disease (CAD) and myocardial infarction (MI).
Section snippets
Patients and controls
The study population comprised individuals of Caucasian origin examined with coronary angiography at Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar der Technischen Universität München and participating in the Risk Evaluation in Subjects Investigated with Coronary Angiography (RESICA) project. Consecutive patients with significant coronary stenoses but without symptoms or signs of old or acute MI constituted the group with CAD (n=998). Consecutive patients with old or
Results
The main baseline characteristics of matched controls, patients with CAD and patients with MI are shown in Table 2. Diabetes mellitus and cigarette smoking were encountered significantly more often in both the patient groups if compared with controls. Arterial hypertension was also more frequent in CAD patients.
The distributions of genotypes did not differ significantly between matched controls, patients with CAD and patients with MI (Table 3). Within each study group, the genotype
Discussion
The main result of this study was that the IL-10 gene polymorphisms −1082G/A, −819C/T, and −592C/A, the TNF-α gene polymorphisms −863C/A and −308G/A, and the TNF-β polymorphism 252G/A had no measurable influence on the occurence of CAD or MI in angiographically evaluated patients. This finding was based on separate analyses of individual alleles, allele combinations, and genotypes.
We observed frequencies of alleles and allele combinations and genotype distributions to be in good correlation
Limitations of the study
Since this study was performed with individuals of Caucasian origin, it has to be determined separately whether or not the results are valid in populations of other ethnic origin. Notably, in a Chinese population, IL-10 promoter allele and haplotype frequencies were found to greatly differ from those in Caucasians [55]. Several lines of evidence suggested that approximately 20-30% of patients who develop an acute coronary event die before arrival at the hospital [56]. For this reason, a
Acknowledgements
The authors thank Angela Ehrenhaff, Marianne Eichinger, Wolfgang Latz, and Gisela Werner for skilful technical assistance.
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2018, Gene ReportsCitation Excerpt :Around the world, association studies have investigated the influence of one Single Nucleotide Polymorphism (SNP) or many SNPs in one gene, which usually resulted in limited and sometimes divergent information that is difficult to replicate in case-control studies across different populations having different genetic background (Rudnicki and Mayer, 2009; Var et al., 2009). Moreover, in case-control studies, the influence of gene-gene and gene environment interactions, as well as the other risk factors, such as gender, age… are poorly considered in evaluating the risk of MI, which may partially explain these conflicting and inconclusive results from such genetic association studies in MI (Lio et al., 2004; Licastro et al., 2004; Chiappelli et al., 2005; Olivieri et al., 2006; Kock et al., 2001; Donger et al., 2001; Bennet et al., 2006; Keso et al., 2001; Howell et al., 2005). Unlike Mendelian diseases that are associated with a single gene, common complex diseases such as MI are likely caused by the non-linear interaction of numerous genetic and environmental risk factors.