Background
Atherosclerosis is a chronic arterial wall inflammatory disease [
1] associated with endothelial dysfunction, intimal hyperplasia, smooth muscle hyperplasia, lipid deposition, plaque formation, and micro-vein formation. Endothelial dysfunction is associated with the expression of chemokines and adhesion molecules, such as vascular cell adhesion molecule-1 [
2]. Cytokines produced in the plaque micro-environment, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF), trigger the recruitment of inflammatory cells [
3]. Chemokines are released by endothelial cells, mastocytes, platelets, macrophages, and lymphocytes [
4]. They mediate the migration of leukocytes to inflamed tissues and control the inflammatory reactions in various immune-mediated diseases. Chemokine expression is associated with atherosclerotic lesion development and vascular remodeling [
5]. Owing to such inflammatory reactions and the accumulation of blood lipids, the artery becomes less elastic and narrower, promoting an atherosclerotic plaque formation. When vascular plaques occur in the coronary artery of the heart, they lead to a coronary artery disease (CAD) [
1]. In recent years, the macrophage migration inhibitory factor (
MIF) has been extensively studied in molecular functional and genetics studies. In 1966,
MIF was identified as a soluble factor secreted by T cells that delayed hypersensitivity reactions and inhibited the random migration of macrophages [
4]. Later studies revealed that MIF is stored in the pituitary gland and secreted during endotoxemia and plays a key regulatory role in innate immunity by counter-regulating glucocorticoids [
6]. It has been currently considered to act as a chemokine-like multidirectional inflammatory cytokine and has been recognized to mediate numerous acute and chronic inflammatory diseases [
7].
MIF is quite ubiquitously expressed and is an upstream immunomodulatory cytokine. It plays an important role in promoting inflammatory responses in CAD [
8], diabetes [
9], rheumatoid arthritis [
10], septicemia [
11], psoriasis [
12], and other diseases. The
MIF gene is located on chromosome 22q11.2, and two functional promoter polymorphisms have been studied [
13]. One is a G-to-C transition at − 173 (rs755622) and the other is a (CATT)
5–8 tetranucleotide repeat at − 794. The
MIF − 173C allele creates a putative binding site for the transcription factor activating enhancer binding protein 4 and is associated with increased
MIF gene expression and protein levels in a cell-type-dependent manner [
14].
However, according to current reports, MIF − 173C/G is closely related to the production and expression of MIF, which causes the occurrence and development of CAD by promote the inflammatory response.
Some studies comparing MIF − 173C/G have found associations with CAD pathogenesis. To overcome the limitations and outcome bias of individual studies, and to address the inconsistencies in the findings among the various studies, we conducted a more comprehensive meta-analysis based on a systematic literature review to confirm whether MIF − 173C/G was associated with increased sensitivity and risk for CAD.
Discussion
CAD, a chronic arterial wall disease, is not simply due to an accumulation of lipids in the body, but is an inflammatory disease in response to an injury, in which inflammatory cells and mediators are involved in plaque formation.
MIF was the first cytokine to be considered an important mediator of chronic inflammatory and autoimmune diseases, mediating the generation of inflammatory cells.
MIF is an important proinflammatory factor and chemokine. It can recruit inflammatory immune cells, such as macrophages and T lymphocytes, to participate in the inflammatory response at atherosclerotic plaques [
26,
27]. It can also stimulate macrophages and lymphocytes to secrete inflammatory factors, including IL-6, IL-8, TNF-α, and intracellular adhesion factor, which significantly enhance the inflammatory response at atherosclerotic plaques [
10].
MIF can be expressed at low levels in vascular smooth muscle cells and vascular endothelial cells, but when atherosclerotic plaques occur in the blood vessels, the production of
MIF increases rapidly, suggesting it may be involved in the occurrence of atherosclerosis. In recent years,
MIF has been explored in genetic and molecular functional studies [
28]. The
MIF -173C allele establishes a hypothetical binding site for transcription factor activating enhancer binding protein 4, which may increase
MIF gene and protein expression [
14].
The MONICA/KORA Augsburg study reported that the
MIF rs755622 C allele increased the susceptibility to juvenile idiopathic arthritis, systemic lupus erythematosus, and celiac disease associated with severe ulcerative colitis [
17,
20,
26,
29]. The hypothesis that
MIF rs755622 polymorphisms regulate
MIF levels only in certain conditions, e.g., in response to infection, trauma, or autoimmunity, was confirmed in a cardiopulmonary bypass study [
30]. Only
MIF -173C allele carriers receiving revascularization and cardiopulmonary bypass had elevated systemic
MIF levels, indicating genotype changes in
MIF expression affected by trauma and injury. Alternatively, rs755622 may be mainly related to localized
MIF expression, that is,
MIF expression can be increased in certain cell types or tissues, such as atherosclerotic lesions. However, there is currently no evidence supporting this speculation.
The mechanistic link between
MIF -173C alleles and disease remains unclear, as most studies focused on genotyping data and did not evaluate circulating
MIF levels. Nevertheless, we can unravel the correlation between
MIF rs755622 polymorphism and CAD based on published articles. One study showed that
MIF -173C was associated with an increased risk CAD in German women, based on an average follow-up period of 10 years [
31]. In the Han Chinese too,
MIF -173C has been identified as a CAD risk factor [
17,
19]. Yang et al. reported that plasma
MIF levels may be used to predict the severity of coronary lesion [
32]. Meanwhile,
MIF -173G/C polymorphism influences the plasma levels of
MIF and TNF-α in some inflammatory disorders [
33,
34]. However, the precise regulatory mechanisms of this association remain unclear. Relevant studies suggest that the
MIF rs755622 G/C polymorphism may play a critical role in the etiology of coronary artery lesions and may have predictive value for their severity. The analysis of more
MIF polymorphisms may help to identify individuals with potential CAD risk, and identifying targeted
MIF variants in CAD patients may be beneficial for risk stratification and management.
In our systematic meta-analysis, including six studies comprising approximately 2700 participants,
MIF -173C/G was associated with CAD risk in the overall population and in two ethnic subgroups (Asians and Caucasians). CAD risk was increased in the allelic, recessive, and homozygote models, whereas it was decreased in the dominant and heterozygote models. To identify and reduce the source of heterogeneity, we analyzed the Asian and Caucasian populations separately. We could conclude that people with
MIF -173C were more likely to develop CAD, which might be related to increased
MIF expression and production, which aggravated the inflammatory reaction, leading to the occurrence and development of CAD. There are several potential causes of the observed heterogeneity. First, study characteristics, including the source population for the case-control groups, race, research design, CAD subtypes, sample size, genotyping methods and specific typing can differ among studies and may explain the differences in subgroup analysis. Second, ethnic groups are genetically different, and clinical manifestations depend on factors such as age, sex, obesity, hypertension, and diabetes, which may be related to CAD heterogeneity [
35]. Third, different populations have different lifestyles, including eating habits, exercise patterns, which may affect CAD onset and progression.
Our meta-analysis had some strengths. First, a comprehensive meta-analysis to provide substantial evidence of the association between MIF -173C/G and CAD, which would allow a more accurate judgment of this gene polymorphism in the treatment of human CAD, had not been conducted to date. Second, we selected Chinese and foreign studies, including two different ethnicities, for which we conducted subgroup analyses, which allowed us to find the source of heterogeneity and further assess the risk of MIF -173C/G for CAD in these two populations. In contrast, our study had several limitations. First, it included only six studies. Therefore, additional information from large-cohort studies on MIF -173C/G and CAD is required to reduce the publication bias. Second, numerous factors can influence the occurrence and development of coronary heart disease, and we did not consider other polymorphisms in MIF, such as -794CATT5–8, or in other related genes. Third, despite the inclusion of different ethnic groups, populations may have different habits, including different eating and lifestyle habits, which should be considered more carefully in future studies. Fourth, more research is needed to confirm the relevance of -173 C/G to the risk of CAD and to clarify the underlying mechanism.
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