Macrophage Migration Inhibitory Factor Polymorphisms Research Articles

The human MIF polymorphism CATT7 enhances pro-inflammatory macrophage polarization in a clinically relevant model of allergic airway inflammation.

High level expression of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow-derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF-dependent, as administration of a small molecule MIF inhibitor, SCD-19, blocked the induction of this pro-inflammatory M1-like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro-inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM-induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8).

Macrophage Migration Inhibitory Factor and Gene Polymorphism (rs755622G>C) in Unstable Vitiligo Patients

Vitiligo pathogenesis is related to the macrophage migration inhibitory factor (MIF) protein. This study aimed to assess the lesional MIF levels and gene polymorphisms (rs755622G>C) in patients with vitiligo. To assess the consequences of combining narrow-band ultraviolet B with oral minipulse prednisolone as opposed to a combination with oral methotrexate on MIF levels in vitiligo patients, 50 unstable vitiligo patients and 50 controls were randomly chosen for comparison. MIF levels in skin homogenates and MIF (rs755622G>C) single nucleotide polymorphisms were assessed using the ELISA and the polymerase chain reaction restriction fragment length polymorphism (RFLP-PCR) techniques. We found significantly higher lesional MIF levels, a higher frequency of both (GC) and (CC) genotypes, and a significantly more frequent mutant allele (C) in patients than in controls. In addition, there was a significantly lower frequency of the allele (C) among patients who exhibited moderate to marked therapeutic improvement than among those who showed minimal to mild improvement. In conclusion, tissue MIF and gene polymorphisms were associated with vitiligo. In addition, oral corticosteroids, narrow-band ultraviolet B, methotrexate-targeted tissue MIF, and gene polymorphisms can improve unstable vitiligo.

Analysis of Macrophage Migration Inhibitory Factor Genotype in Hemophilia a Patients.

Hemophilia A, an X-linked bleeding disorder, is caused by a complete or partial deficiency in factor VIII. Multiple factors engage in the development and progression of bleeding episodes in hemophilia patients, especially arthropathy. Detection of macrophage migration inhibitory factor (MIF)-173 G/C polymorphism in people with hemophilia A (PWH) and the possible associations between the type of MIF gene polymorphism and selected disease-related variables. This case-control study included 95 male patients with hemophilia A and 95 non-hemophiliac subjects, all aged from 2 months to 63 years. An allele-specific polymerase chain reaction (AS-PCR) with a multiplex technique was used to detect MIF polymorphisms. A significantly higher frequency of GG polymorphism was reported in the control group (81, 85.3%) compared to PWH (64, 67.4%), while a significantly higher frequency of GC polymorphism was found in PWH (21, 22.1%) than that in healthy subjects (10, 10.5%), P < 0.05. The G allele polymorphism was detected in 90.0% of the control group compared to 78.4% of PWH (149 subjects), while the C allele frequency was higher in PWH (41, 21.6%) compared to that in healthy individuals (18, 10.0%), P < 0.05. The frequencies of varied MIF-173 polymorphisms did not show significant differences among patients with different clinical presentations or in relation to presence of inhibitors, P > 0.05. MIF-173 GC polymorphism is seen in PWH more than that in healthy individuals. Further studies are required to detect additional SNPs through sequencing of the MIF gene and to detect MIF serum levels during bleeding episodes.

Macrophage Migration Inhibitory Factor in Major Depressive Disorder: A Multilevel Pilot Study.

Macrophage migration inhibitory factor (MIF) is a controversially discussed inflammatory marker in major depressive disorder (MDD). While some studies show an association of high MIF protein levels with depression, animal models have yielded conflicting results. Thus, it remains elusive as to whether MIF plays an anti- or pro-depressive role. Therefore, we aimed to examine the potential of MIF at the genetic, expression and protein levels as a risk factor and biomarker to diagnose, monitor, or predict the course of MDD. Patients with a current major depressive episode (n = 66 with, and n = 63 without, prior medication) and remitted patients (n = 39) were compared with healthy controls (n = 61). Currently depressed patients provided a second blood sample after three weeks of therapy. Depression severity was assessed by self-evaluation and clinician rating scales. We genotyped for three MIF polymorphisms and analyzed peripheral MIF expression and serum levels. The absence of minor allele homozygous individuals in the large group of 96 female patients compared with 10-16% in female controls suggests a protective effect for MDD, which was not observed in the male group. There were no significant group differences of protein and expression levels, however, both showed predictive potential for the course of depression severity in some subgroups. While MIF protein levels, but not MIF expression, decreased during treatment, they were not associated with changes in depression severity. This project is the first to investigate three biological levels of MIF in depression. The data hint toward a genetic effect in women, but do not provide robust evidence for the utility of MIF as a biomarker for the diagnosis or monitoring of MDD. The observed predictive potential requires further analysis, emphasizing future attention to confounding factors such as sex and premedication.

Macrophage migration inhibitory factor gene promoter polymorphism (−173G/C SNP) determines host susceptibility and severity of leptospirosis

The biological mechanisms that are associated with the severity of leptospirosis are far from complete. The aim of the present study was to investigate whether the macrophage migration inhibitory factor (MIF) gene promoter polymorphisms determine susceptibility to and severity of human leptospirosis. MIF is a potent pro-inflammatory cytokine, which has been reported to correlate with the risk of inflammatory disease onset and severity. In the present study, MIF 173G/C single nucleotide polymorphism (SNP) was analyzed by PCR-RFLP (Restriction fragment length polymorphism). A statistically significant increase of MIF -173*C allele related genotypes was observed in leptospirosis patients when compared with healthy control subjects. Genotypes GC (OR: 28.4; 95% CI: 10.9–73.6; p < 0.001) and CC (OR: 40; 95% CI: 2.3–686.5; p < 0.001) of −173 G/C MIF polymorphism was associated with susceptibility and severity of leptospirosis respectively. In leptospirosis cases, 69.8% of leptospirosis patients were GC genotype carriers while 19.8% and 10.4% cases were CC and GG carriers; in severe leptospirosis, 68% cases were CC carriers and 32% were GC carriers; and in healthy controls, 92.5% subjects were GG carriers and 7.5% were GC carriers. MIF -173*C allele was (OR: 15; 95% CI: 6.1–36.8; p < 0.001) significantly associated with the risk of leptospirosis than −173*G allele (OR: 0.06; 95% CI: 0.02–0.16; p < 0.001). The relationship of −173G/C MIF polymorphism with mRNA and serum level of MIF and inflammatory cytokine expression was analyzed by quantitative real-time PCR and MIF ELISA. MIF mRNA expression was significantly increased in carriers of MIF -173*C allele associated genotypes, GC and CC. A substantial increase of serum MIF (Mean ± SD) was found in risk genotypes GC (5.81 ± 0.61 ng/mL) and CC (10.12 ± 0.23 ng/mL) carrying leptospirosis patients than GG genotype (0.86 ± 0.3 ng/mL) carrying healthy controls. Pearson correlation test showed a significant positive correlation between elevated serum MIF and −173*C allele (r = 0.99, p < 0.001). High MIF expression genotypes GC and CC upregulated the mRNA expression of TNF-α, IL-1β and IL-4 whereas downregulated the IL-10 expression. Thus, MIF -173 G/C SNP genotype GC carriers have highly susceptible to leptospirosis and the leptospirosis patients with CC genotype had an increased risk of developing a severe form of the disease. The observations of this study conclude that MIF -173G/C polymorphism is associated with leptospirosis susceptibility and severity and also could be a promising severity predictor of leptospirosis.

ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus.

Macrophage migration inhibitory factor (MIF) is an inflammatory and neurorendocrine mediator that counterregulates glucocorticoid immunosuppression. MIF polymorphisms, which comprise a variant promoter microsatellite (-794 CATT5-8 ), are linked genetically to autoimmune disease severity and to glucocorticoid resistance. While invasive stimuli increase MIF expression, MIF also is up-regulated by glucocorticoids, which serve as a physiologic regulator of inflammatory responses. This study was undertaken to define interactions between the MIF promoter, the glucocorticoid receptor (GR), and the transcription factor inverted CCAAT box binding protein 90 kd (ICBP90) (also referred to as UHRF1), which binds to the promoter in a -794 CATT5-8 length-dependent manner, to regulate MIF transcription. Interactions of ICBP90, GR, and activator protein 1 (AP-1) with MIF -794 CATT5-8 promoter constructs were assessed by coimmunoprecipitation, Western blotting, and genetic knockdown. Nuclear colocalization studies were performed using anti-transcription factor antibodies and confocal microscopy of glucocorticoid-treated cells. MIF transcription was studied in CEM-C7 T cells, and the impact of the MIF -794 CATT5-8 microsatellite variation confirmed in peripheral blood T cells and in rheumatoid synovial fibroblasts of defined MIF genotype. Functional interactions were quantified by apoptosis and apoptotic signaling in high- and low-genotypic MIF-expressing human cells. We defined functional interactions between the transcription factors ICBP90, the GR, and AP-1 that up-regulated MIF transcription in a -794 CATT5-8 length-dependent manner. Experimental reduction of ICBP90, GR, or AP-1 decreased MIF expression and increased glucocorticoid sensitivity, leading to enhanced apoptosis in T lymphocytes and in rheumatoid synovial fibroblasts. These findings suggest a mechanism for genetic variation of glucocorticoid-regulated MIF transcription, with implications for autoimmune disease severity and glucocorticoid responsiveness.

Levels of the macrophage migration inhibitory factor and polymorphisms in systemic lupus erythematosus: a meta-analysis.

IntroductionSeveral published results have established variations in respect to plasma/serum macrophage migration inhibitory factor (MIF) levels and gene polymorphisms with systemic lupus erythematosus (SLE). This study gave a more concise estimation on the MIF levels for SLE patients and established the association between MIF polymorphisms and SLE.Material and methodsAll articles were searched from PubMed, Embase, Web of Science, Wan-Fang, Chinese Biological Medical Literature, and China National Knowledge Infrastructure up to 6th October 2017, with no language restriction. Pooled standard mean difference with 95% confidence interval was evaluated using random effect model. Thirteen articles were used for this meta-analysis, with 620 SLE patients and 779 healthy controls assessed for MIF levels, and 2,159 SLE patients and 2,574 healthy controls considered for MIF-173 C/G and MIF-794 CATT polymorphisms.ResultsThere was a significant higher MIF levels in SLE patients than in healthy controls (p = 0.004). The subgroup analysis showed Asians and ages < 30 had higher MIF levels in SLE patients than in healthy controls. It was evident that patients with systemic lupus erythematosus diseases activity index scores < 8 and ≥ 8, and disease duration for both year < 5 and ≥ 5 of SLE had higher MIF levels when compared to healthy controls. We found a significant association between SLE and MIF-173 C/G, but not MIF-794 CATT.ConclusionsThis study provided evidence of significant higher MIF levels in SLE patients and supported the association of MIF-173 C/G and SLE. However, we were not able to establish an association between MIF-794 CATT and SLE.

MIF promoter polymorphism increases peripheral blood expression levels, contributing to increased susceptibility and poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. The etiology and pathogenesis of HCC remain unclear. Macrophage migration inhibitory factor (MIF) plays a critical role in the pathogenesis of hepatocellular carcinoma. The association between MIF polymorphisms and its expression level in HCC has rarely been demonstrated. In the present study, the peripheral blood of 202 patients with HCC (HCC group), 242 patients with chronic hepatitis B (CHB group), 215 patients with liver cirrhosis (LC group) and 227 healthy volunteers (normal group) were collected, DNA was extracted and the target fragment of MIF gene was amplified using PCR. The products were then sequenced, and the expression levels of MIF protein were tested using ELISA. The results showed that the MIF rs755622 polymorphism was associated with an increased susceptibility and metastasis of HCC, and that the genotypes GC and CC were associated with poor prognosis of HCC. Compared with the normal, CHB and LC groups, the expression of MIF in the peripheral blood of the HCC group was significantly increased, and the high expression was associated with to poor prognosis. In the HCC group, MIF protein levels for genotypes GC and CC were increased compared with those of genotype GG. The current study indicated that the MIF rs755622 polymorphism is associated with susceptibility and metastasis of HCC, and that the GC and CC genotypes may be indicators of poor prognosis, which may be ascribed to the MIF rs755622 polymorphism leading to elevated MIF protein expression in peripheral blood.

Influence of MIF polymorphisms on CpG island hyper-methylation of CDKN2A in the patients with ulcerative colitis

BackgroundCDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572).MethodsOne hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14ARF and p16INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP.ResultsWe found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14ARF or p16INK4a. Carrying the rs755622 C allele indicated a significantly higher risk for p14ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08–4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14ARF and p16INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25–6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55–262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12–17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46–144.3; p = 0.022).ConclusionsTaken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.

MIF\xa0-173G/C (rs755622) polymorphism modulates coronary artery disease risk: evidence from a systematic meta-analysis

BackgroundCoronary artery disease (CAD) remains one of the major causes of death in humans. Genetic testing may allow early detection and prevention of this disease. This study aimed to investigate the association between the macrophage migration inhibitory factor (MIF) -173G/C (rs755622) polymorphism and susceptibility to CAD based on a meta-analysis.MethodsWe searched several databases to identify observational case-control studies investigating the association between the MIF -173G > C (rs755622) polymorphism and CAD risk published before July 30, 2019. Data were analyzed using the STATA software.ResultsSix studies, comprising a total of 1172 CAD cases and 1564 controls evaluated for MIF polymorphisms, were included. The occurrence of CAD was found to be associated with the C allele of the MIF rs755622 SNP in the total population (C/G, OR = 1.489, 95% CI = 1.223–1.813). Further, MIF –173G/C polymorphism was significantly associated with CAD under the allelic model in the Asian (C/G, OR = 1.775, 95% CI = 1.365–2.309) and Caucasian (C/G, OR = 1.288, 95% CI 1.003–1.654) subgroups. The data showed that the risk of CAD was higher in the population carrying the C allele.ConclusionsWe found evidence of associations between MIF -173C/G and CAD susceptibility in the Asian and Caucasian populations.

Macrophage migration inhibitory factor gene polymorphisms as exacerbating factors of apical periodontitis.

Two polymorphisms in the macrophage migration inhibitory factor (MIF) gene have been associated with inflammatory diseases (-794 CATT5-8 and -173G>C); however, so far there are no reports of studies related to oral health. To genotype the -794 CATT5-8 and -173G>C MIF polymorphisms in Mexican patients with apical periodontitis as a genetic risk of exacerbation. The study involved 120 patients with apical periodontitis: 60 with a diagnosis of acute apical periodontitis (Group A) and 60 without previous episodes of exacerbation (Group B). Allelic discrimination was performed from peripheral blood DNA; the repeat polymorphism -794 CATT5-8 was genotyped with sequencing, while the -173G>C polymorphism was determined using real-time polymerase chain reaction (RT-PCR) using TaqMan probes. The associations between MIF polymorphisms, haplotypes and the risk of exacerbated apical periodontitis were assessed. The allele CATT7 was associated with the risk of a stage of acute inflammation (OR = 4.13; 95% CI = 1.82-9.63; p =< 0.001). Regarding the -173G >C polymorphism, a process of inflammation exacerbation was only associated with the CC genotype (OR = 4.1; 95% CI = 1.02-20.84; p = 0.045). The analysis of the haplotype showed that the combination CATT7/C increases the risk of exacerbation of apical periodontitis (OR = 3.57; 95% CI = 1.038-13.300; p = 0.021). The polymorphisms -794 CATT5-8 and -173G>C MIF seem to significantly influence the development of a state of exacerbated inflammation in patients with apical periodontitis.

The Relationship between Functional Promoter Variants of Macrophage Migration Inhibitory Factor and Endometriosis.

Objective Endometriosis is a common gynecological and inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is secreted by accumulated active macrophages in ectopic endometrial tissues. Two promoter polymorphisms of MIF [-794(CATT)5–8/-173G/C] were identified to susceptibility and severity of several immune and inflammatory diseases. We aimed to evaluate the possible association between MIF promoter polymorphisms and susceptibly to endometriosis and its corolation with mRNA level. Materials and Methods This case-control study was performed in Royan Institute from 2015 to 2017. Polymorphisms were evaluated in 106 endometriosis patients and 110 controls. For 17 endometrioma tissues, gene expression studies were conducted during secretory phase of menstrual cycle. Restriction fragment length polymorphism (RFLP) analysis was performed to determine -173G/C polymorphism and -794(CATT)5–8 were detected by sequencing. Quantitative polymerase chain reaction (Q-PCR) was carried out to determine MIF expression level. Results Homozygote of CATT7 was observed only in endometriosis whilst we did not detect the significant allele and genotype variation in both groups. The homozygotes for -794(CATT)5–8 and -173G/C polymorphisms were obtained to estimate the haplotype frequencies. Significantly higher haplotype frequencies were observed for CATT5/G in controls [global P value=0.044]. Additionally, the CATT5/C and CATT7/G haplotypes were not detected in any groups. Expression level of mRNA in ectopic tissue of endometriosis patients with CATT6,7/CC haplotype, were significantly higher compared to other haplotypes including CATT5,5/GG (2.91 fold, P=0.007), CATT5,5/GC (2.48 fold, P=0.047) and CATT6,6/GG (2.08 fold, P=0.046). ConclusionWe report, for the first time, a strong linkage between the decreased repetition of CATT and G allele in control and CATT6/C and CATT7/C haplotypes in endometriosis patients. Increased MIF expression is affected by genetic variants in the MIF promoter in ectopic endometrial tissues. This promoter haplotype might play an important role in the development and establishment of endometriosis.

Macrophage Migration Inhibitory Factor (MIF) Gene Polymorphism of Urothelial Carcinoma Patients in Iraq

Bladder cancer is the 2nd most frequent malignancy of the genitourinary tract and the fourth most common cancer in men . This study was designed to shed light on the association between polymorphism of macrophage migration inhibitory factor (MIF) gene at -173 locus as risk factor of bladder cancer in Iraqi population by PCR-RFLP. In a hospital-based case-control study of 70 patients with bladder cancer and 30 cancer-free controls frequency-matched by age, sex, smoking status, and alcohol use, we genotyped the MIF polymorphism and analyzed immunohistochemical stained operational bladder cancer tissue sections for MIF. We found that individuals with GC/GG genotype had a significantly decreased risk of bladder cancer ( OR = 1.55, 95% CI, 0.498 to 8.85) than those with CC genotype. The frequencies of the C allele on the MIF gene were significantly increased in Urinary bladder carcinoma patients. MIF -173G&gt;C polymorphism may play a role in the etiology of bladder cancer in Iraqi.

Association of the genetic variants (-794 CATT5-8 and -173 G>C) of macrophage migration inhibitory factor (MIF) with higher soluble levels of MIF and TNFα in women with breast cancer.

BackgroundFunctional variants ‐173 G > C (rs755622) and ‐794CATT5‐8 (rs5844572) MIF gene have been associated with the risk in several types of cancer, as well as with the increase of soluble levels of MIF and TNFα. However, in previous studies contradictory and uncertain results have been presented on the implication of MIF polymorphisms with the association in cancer, specifically in breast cancer (BC). We investigated whether the variants are associated with the susceptibility to develop BC and the soluble levels of MIF and TNFα in women with BC from western Mexico.Materials and methodsA total of 152 women with BC and 182 control subjects (CS) were enrolled in this study. The determination of genotypes ‐173 G > C and ‐794 CATT5‐8 MIF polymorphisms was performed by PCR‐RFLP and PCR, respectively. In addition, the soluble levels of MIF and TNFα in both studied groups were quantified by ELISA and MILLIPLEX assay, respectively.ResultsThe most frequent allele found in BC was the G (74.3%) and 6 (54%) in the variants ‐173G > C and ‐794 CATT5‐8, respectively, without significant differences in both groups. Nevertheless, the women with BC carriers ‐173*C and ‐794CATT7 have higher levels of MIF in comparison with CS. An increase of MIF (BC: 11.1 ng/mL vs CS: 5.2 ng/mL, P < .001) and TNFα (BC: 24.9 ng/mL vs CS: 9.9 pg/mL, P < .001) was found.ConclusionThe functional variants of MIF are not genetic susceptibility markers for BC. Nevertheless, the alleles ‐173*C and ‐794CATT7 are associated with the increase of MIF circulating in women with BC.

Polymorphism in Macrophage Migration Inhibitory Factor -173GC in Pediatric Patients with Autoimmune Hepatitis

PurposeAutoimmune hepatitis (AIH) is a chronic disease that may lead to cirrhosis. The immunopathogenesis of AIH is not fully understood and it mainly involves T-cell mediated mechanism. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that promotes T cell response and its polymorphism may serve as a severity marker of AIH. No previous study has considered investigating MIF polymorphism in children with AIH.MethodsForty-two children with definite diagnosis of AIH were enrolled along with 100 age and sex matched controls. All participants were tested for polymorphism at -173GC (rs755622) of MIF gene. All patients received the standard protocol of steroid plus azathioprine to achieve remission. Liver biopsy was performed at time of diagnosis for all patients and only 18 of them underwent a second biopsy after treatment.ResultsNo statistically significant differences in the frequency of the genotypes GG and GC or in allele distribution were found in both patient and control groups (p=0.590, 0.640 respectively). Initial alanine aminotransferase (ALT) levels at the time of presentation was significantly higher in the GC group than GG group (p=0.020). GC genotype significantly correlated with disease relapse (r=0.41, p=0.007). Regression of necroinflammation and the fibrosis score in the second liver biopsy was statistically significant in the GG group (p<0.0001, p=0.010 respectively).ConclusionMIF -173GC polymorphism is associated with clinically significant markers of pediatric AIH, including increased initial serum ALT levels, may help predict necroinflammatory/fibrosis regression effectively, following immunosuppressive treatment.

Correlations of MIF polymorphism and serum levels of MIF with glucocorticoid sensitivity of sudden sensorineural hearing loss.

ObjectiveThis study explored the relationship between macrophage migration inhibitory factor (MIF) gene polymorphism (−173G/C) and glucocorticoid sensitivity in sudden sensorineural hearing loss (SSNHL).MethodsA total of 120 patients with SSNHL were divided into a glucocorticoid-sensitive group and a glucocorticoid-resistant group. A group of 93 healthy individuals served as the control group. Serum MIF levels of the participants were measured and MIF genotyping was performed.ResultsThe frequency of the MIF −173C allele was significantly higher in glucocorticoid-sensitive patients than in glucocorticoid-resistant patients. Serum MIF levels were significantly higher in SSNHL patients than in healthy controls, and higher in the glucocorticoid-sensitive group than in the glucocorticoid-resistant group of SSNHL patients, which was unexpected. Compared with patients with the GG genotype, patients with the −173C allele (GC and CC genotypes) had significantly higher levels of serum MIF and superoxide dismutase activity and lower levels of tumor necrosis factor-α and malondialdehyde.ConclusionThe MIF −173G/C polymorphism is associated with glucocorticoid sensitivity in SSNHL patients. The C allele can result in higher MIF production, reduced oxidative stress, and greater glucocorticoid sensitivity.

A novel gene-wide haplotype at the macrophage migration inhibitory factor (MIF) locus is associated with endometrioma

ObjectiveEndometriosis is a common complex gynecological disorder that may result in infertility. Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is overexpressed in endometriosis tissues. However, hitherto, no study tested the possible relevancy at genetic level. The aim of this study was to evaluate MIF polymorphisms and possible associations between haplotype of the gene and endometrioma. Study designIn this experiment, 115 patients with confirmed endometrioma and 120 of women who were not diagnosed with endometrioma were recruited for this case-control genetic association study. The coding region of MIF was resequenced to detect variations of potential significance. Restriction fragment length polymorphism was used to type the −173 G/C (rs755622) promoter Single nucleotide polymorphism (SNP). Haplotype analyses were then undertaken to assess the effect of genetic variations. ResultsWe detected one functional SNP in promoter (rs755622) and non-functional mutations across the gene including (rs2096525, rs182012324, rs33958703 and rs2070766) in our samples. However, haplotype analysis showed a significant association between MIF and endometrioma where a single haplotype CC carrying only the minor allele at −173 G/C was significantly over-represented in the patients group (P = 0.007) and remained significant even after correction for (Bonferroni adjusted P = 0.028). ConclusionWe report a strong linkage between a novel MIF haplotype and endometrioma. This association is consistent with expression data at both transcript and protein levels suggesting the −173C/G promoter as a critical factor.

Macrophage migration inhibitory factor promoter polymorphisms are associated with disease activity in rheumatoid arthritis patients from Southern Mexico.

BackgroundMacrophage migration inhibitory factor (MIF) is a cytokine capable of stimulating inflammatory cytokine and matrix metalloproteinase production from macrophages and synovial fibroblasts, which leads to persistent inflammation and bone degradation, two of the major pathological processes in rheumatoid arthritis (RA). The aim of this study was to evaluate the association of MIF promoter polymorphisms (−794CATT5‐8 rs5844572 and −173G > C, rs755622), circulating MIF levels, and mRNA expression with RA susceptibility and disease activity.MethodsA case–control study was conducted in 200 RA patients and 200 control subjects (CS) from Southern Mexico. Genotyping was performed by conventional PCR and PCR‐RFLP methods. MIF mRNA expression was quantified by real‐time PCR and MIF serum levels were determined by an ELISA kit.ResultsThe 7,7 (−794CATT5‐8) and −173CC (−173G > C) genotypes were associated with higher disease activity in RA patients. MIF serum levels were increased, and MIF mRNA expression was reduced in RA patients as compared to CS. In addition, RA patients with moderate disease activity had higher MIF levels than those with low disease activity. The −794CATT5‐8 and −173G > C MIF polymorphisms were not associated with RA susceptibility.ConclusionThese results suggest an important role of MIF polymorphisms and MIF serum levels with disease activity in RA.

2598. Macrophage Migration Inhibitory Factor May Contribute to Disseminated Coccidioidomycosis Susceptibility

BackgroundDisseminated coccidioidomycosis occurs in <1% of cases, and genetic polymorphisms may account for some of the variability in infection severity. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with two promoter polymorphisms linked to variability in expression. High expression MIF polymorphisms have been associated with granulomatosis with polyangitis (GPA), sarcoidosis and tuberculosis. Despite the overlap between MIF and Coccidioides immunity, MIF has never been studied in coccidioidomycosis.MethodsA549 cells transfected with MIF promoter/luciferase plasmids of 0 or 8 CATT repeats were stimulated with 50 µg/mL of inactivated C. posadasii spherule lysate, and luciferase expression was measured as relative units (RU) of luminescence. Genomic DNA from patients with disseminated coccidioidomycosis (n = 37) and healthy controls (n = 371) was analyzed for the 794 CATT5-8 microsatellite and the -173 G/C SNP. Cohorts were divided into self-identified African Americans and Caucasians, and allele frequencies were compared using Fisher exact test. Plasma MIF levels were analyzed by enzyme-linked immunosorbant assay using specific antibodies, and levels were compared by T-test.ResultsHuman lung epithelial cells exposed to Coccidioides spherules had significantly higher MIF expression than unexposed cells (3.94 ± 0.44 vs. 3.02 ± 0.24 RU, P = 0.0162). Among Caucasians (n = 26), the high MIF expression −173C containing genotype was present in 50% of the coccidioidomycosis patients vs. 40% of healthy controls (P = 0.396). The -794 CATT7 containing genotype was present in 40% of patients vs. 27% of controls (p = 0.240). Plasma MIF levels were higher in coccidoidomycosis patients with high- vs. low-expression alleles (P = 0.008), but lower in patients vs. controls (P < 0.0001).Conclusion Coccoidioides spherules stimulated MIF expression in human lung epithelial cells supporting the hypothesis that MIF is involved in immunity against this pathogen. In Caucasian subjects, the higher MIF expression genotypes were more common in patients with disseminated coccidioidomycosis when compared with healthy controls, although significance was limited by sample size. This is consistent with high expression MIF alleles associated with other granulomatous diseases, and may reflect destruction of the granuloma with pathogen dissemination.Disclosures All authors: No reported disclosures.

Genetic Variants in the Promoter Region of the Macrophage Migration Inhibitory Factor are Associated with the Severity of Hepatitis C Virus-Induced Liver Fibrosis.

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF)—rs755622 and rs5844572—exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT5–8 were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; p = 0.03). Additionally, ≥7 microsatellite repeats were associated with lower fibrosis stages (<F2) (p = 0.04). Comparable tendencies were observed in the second independent cohort, where fibrosis was assessed using transient elastography. However, once cirrhosis had been established, the C/C genotype and higher microsatellite repeats correlated with impaired liver function and a higher prevalence of hepatocellular carcinoma. Our study demonstrates that specific MIF polymorphisms are associated with disease severity and complications of HCV-induced fibrosis in a stage- and context-dependent manner.