The Role of MIF-173G/C Gene Polymorphism in the Susceptibility of Autoimmune Diseases

Some certain genetic polymorphisms have been considered to implicate in the pathogenesis and progression of autoimmune diseases and may predispose to an early stage of general autoimmune susceptibility. Recent studies have been conducted to investigate the association between macrophage migration inhibitory factor- (MIF-) 173G/C gene polymorphism and autoimmune diseases; however, the results were not exactly identical. In the present study, a systematic review and meta-analysis of case-control studies was performed to estimate the relationship. A comprehensive search of PubMed, Ebsco, EMbase, WanFang databases and CNKI was done. Odds ratio (ORs) and corresponding 95% confidence intervals (CIs) were combined to pool the effect size. The publication bias was examined by Begg's funnel plots and Egger's test. RevMan 5.3 and STATA 12.0 software were used for statistical processing. 23 papers were included, and the results revealed that MIF-173G/C was significantly associated with an increased risk of autoimmune diseases in five genetic models (recessive genetic model: OR = 1.95, 95% CI: 1.52-2.50; dominant genetic model: OR = 1.35, 95% CI: 1.24-1.46; allele model: OR = 1.32, 95% CI: 1.23-1.41; homozygote model: OR = 1.92, 95% CI: 1.57-2.35; heterozygote model: OR = 4.92, 95% CI: 4.03-6.02), whether in Asia, Europe, or North America. Furthermore, subgroup analysis showed an increasing risk in rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn's disease (CD), atopic dermatitis (AD), Henoch-Schonlein purpura (HSP), and Henoch-Schonlein purpura nephritis (HSPN), but it was not related to the susceptibility of autoimmune hepatitis (AIH). Therefore, it could be considered that MIF-173G/C polymorphism could increase the susceptibility of autoimmune diseases, while there may be the discrepancy of disease entity.


Introduction
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine mainly released from Th2 cells and macrophages, which can mediate the host response to infection and stress by activating innate and adaptive immune pathways [1,2]. In humans, MIF is encoded by a single gene located on chromosome 22q11.2m, a 12 kD peptide comprising 114 amino acids [3]. It mainly interacts with its receptor CD74 to form a complex with CD44, which can result in the lasted activation of the ERK-MAPK pathway by a Src tyrosine kinase signal transduction. Downstream effects of this pathway include NFκB translocation to the nucleus, upregulation of PLA2 and prostaglandins, and stimulation of the arachidonic acid pathway [4]. So far, a single-nucleotide polymorphism in the 50 regions of the MIF gene, MIF-173G/C, a G to C transversion within the MIF promoter region at position -173 creates an AP4 transcription factor binding site [5,6]. Previous studies have shown that MIF-173G/C polymorphism was related to the susceptibility of cancer [7], tuberculosis [8], and coronary atherosclerosis [9]. Recently, many studies have indicated that MIF-173G/C is associated with the pathogenesis and progression of autoimmune diseases.
The autoimmune diseases (AID) are characterized by dysfunction of the immune system leading to the loss of immune tolerance against self-tissues, the presence of autoreactive T and B cells, and a complex pathogenesis of multifactorial etiology, whereas genetic, epigenetic, and environmental factors are together responsible for the onset of AID [10,11]. So far, we have come to understand that certain genetic factors, including genetic polymorphisms implicated in autoimmune diseases, may predispose to an early stage of general autoimmune susceptibility [12]. It has been a new hot spot about the relationship between MIF-173G/C and autoimmune diseases. In Graves' disease (GD), MIF-173G/C plays a dual effect, which is not only a risk factor for the morbidity of goiter but also a protective role in the development of untreated severe goiter [13]. It was considered that MIF-173G/C might play an important role in the susceptibility of UC, but not in CD [14]. Due to the divergence of the researches, we resolved on devising a meta-analysis to evaluate the relationship between them.

Literature Research.
A comprehensive document search was conducted in the PubMed, Ebsco, Embase, and Chinese WanFang databases and China National Knowledge Infrastructure (CNKI) in view of the relationship between MIF-173G/C and autoimmune diseases from the inception to October 10, 2019. The search strategy used in the present study was "macrophage migration inhibitory factor OR MIF" AND "polymorphism OR variant OR mutation" AND "rs755266" AND "Autoimmune disease OR autoimmune disorder OR AD OR AID." The language is restricted to English and Chinese, and the study manually retrieves references from the study and the latest review.

Eligibility Criteria.
In the present meta-analysis, the included literatures must meet the flowing criteria: (1) case-control study or cohort study was published publicly; (2) the study must assess the association of MIF-173G/C gene polymorphism with the susceptibility of autoimmune diseases; (3) the experimental and control subjects involved in studies are human being; and (4) the odds ratios (ORs) and 95% confidence intervals (95% CIs) could be calculated by sufficient genotypic frequencies available in the studies. We applied the Preferred Reporting Items for Systematic Review and Meta-analysis statement (PRIMSA) for the meta-analysis.

Exclusion Criteria.
We excluded the relevant documents according to the following standards: (1) duplicate publications, reviews, meta-analysis, letters, and editorial comments; (2) non-case-control study; (3) animal experiment; and (4) failure to offer the genotypic or allelic frequencies.
2.4. Data Extraction. Two investigators selected literatures independently by checking the title, abstract, and full text based on the eligibility and excluded criteria and ironed out the differences by discussing. And then the following contents were extracted: first author's name, year of publication, country of origin, disease species, genotyping method, the total number of controls and cases, the genotypic and allelic frequencies in controls and cases, and Hardy-Weinberg equilibrium (HWE) test results in controls.
The quality evaluation of literature involved in the present meta-analysis also was done by two investigators in the light of Newcastle-Ottawa Scale (NOS) [15]. We evaluated the quality from the following three aspects: subject selection, comparability of subjects, and clinical outcomes. The aggregate score is 9 points, and the research of high quality is more than 6 points.

Statistical Analysis.
In the present study, HWE was used to evaluate the controls of all the included literatures by the chi-square test, and P > 0:05 was considered the genetic balance in the population. The pooled odds ratio (ORs) and corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the association between MIF-173G/C and autoimmune diseases in the following five genetic models: recessive genetic model (CC vs. GC+GG), dominant genetic model (CC+GC vs. GG), allelic genetic model (C vs. G), heterozygous genetic model (GC vs. GG), and homozygous genetic model (CC vs. GG). The conspicuous level of statistic was assessed by a Z-test with P < 0:05. The heterogeneity was assessed by Cochran's Q statistic and I-squared (I 2 ) metric. The random effects model was selected when there is statistical heterogeneity with P < 0:10 or I 2 > 50%. Otherwise, the fixed effects model is used for the merger analysis. We sequentially eliminated the single document to estimate the sensitivity by screening the OR and heterogeneity. Otherwise, subgroup analyses were performed by disease and area (Asian, Europe, and North America). Potential publication bias was assessed by Begg's funnel plots and Egger's test, and P < 0:05 was considered when there was significantly statistical publication bias. The calculation of ORs, 95% CI, heterogeneity, and sensitivity analysis was conducted by using the software Review manager (Rev-Man, version 5.3, Cochrane Collaboration, Copenhagen, Denmark). The subgroup analysis, Begg's funnel plots, and Egger's test were performed by the STATA 12.0 software (STATA Corp LP, College Station, USA).

3.2.
Results of Meta-analysis. 5559 cases and 7335 controls were involved in the ultima meta-analysis. There was no significant heterogeneity between the MIF-173G/C polymorphism and autoimmune diseases (both P > 0:1), so the fixed effects model was used for meta-analysis. The polled sum-mary crude odds radios (ORs) and corresponding 95% confidence intervals (CIs) in all genetic models were as follows:  Table 3.

Discussion and Conclusion
MIF is an immunoregulatory cytokine secreted from various types of cells in different tissues, which can promote leukocyte recruitment and subsequently promote the expression and function of multiple cytokines and chemokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), CXCL1, and CCL2 [37]. Recently, MIF has been reported to be a key response regulator which can directly activate immune cells or participate in activation pathways initially triggered by other factors [38]. A functional singlenucleotide polymorphism (SNP) was identified in the untranslated 5′region of MIF gene at position -173 consisting of a G to C transition [39]. The new research about the variate action of MIF-173G/C in different diseases was conducted and revealed that MIF-173G/C polymorphism could weakly mediate the development of metabolic syndrome and significantly predict the risk of death by inducing low-grade inflammation independently in Turkish man, but not in woman [40]. Furthermore, the carriage of MIF-173C was associated with unfavorable outcome and death in pneumococcal meningitis, demonstrating strongly that MIF alleles were a genetic marker of morbidity and mortality of pneumococcal meningitis [41].
At present, more and more researchers pay more attention to the roles of MIF-173G/C in autoimmune diseases. The level of MIF-173G/C in progressive multiple sclerosis (MS) is significantly increased in male, suggesting that it can be a sex-specific disease modifier and its receptor CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of two sexes [42]. In systemic lupus erythematosus (SLE), MIF-173C genotype may be a protective factor. However, the high expression of MIF polymorphisms is associated with an increased incidence of end-organ injury in Caucasians and African Americans [43]. And another study reported that MIF-173CC allele might increase the risk for RA, especially among CRP-negative patients in China [44]. In order to systematically elucidate the relationship between MIF-173G/C and autoimmune diseases, we designed the present meta-analysis.
The subgroups categorized by area demonstrated significant associations between MIF-173G/C and autoimmune diseases in Asia, Europe, and North America. In Asia, a strong pooled OR was detected in the recessive model (OR The abovementioned results indicated that the high expression of MIF-173G/C could increase the prevalence of autoimmune diseases whether in Asia, Europe, or North America. Additionally, the association was detected in all 5 genetic models especially in Asia, which revealed that MIF-173G/C could increase the susceptibility of autoimmune diseases more significantly compared with that in Europe and North America. Therefore, it can be considered that there may be regional differences.  In conclusion, the present study verified that there was a significant relationship between MIF-173G/C single-nucleotide polymorphism and the susceptibility of autoimmune diseases, whether in Asia, Europe, or North America. MIF-173G/C can be used as a potential therapeutic target in the treatment prescription of autoimmune diseases. However, in different autoimmune diseases, MIF-173G/C fulfilled various functions. So welldesigned studies with larger sample size are needed to explore the specific mechanism in which MIF-173G/C affects the pathogenesis of different autoimmune diseases.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
The authors declare no conflict of interest.