Migration Inhibitory Factor Promoter Polymorphisms Research Articles

Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis

Background & AimsMacrophage migration inhibitory factor (MIF) is an inflammatory cytokine and an important regulator of innate immune responses. We hypothesised that serum concentrations of MIF are associated with disease severity and outcome in patients with decompensated cirrhosis and acute-on-chronic liver failure (ACLF).MethodsCirculating concentrations of MIF and its soluble receptor CD74 (sCD74) were determined in sera from 292 patients with acute decompensation of cirrhosis defined as new onset or worsening of ascites requiring hospitalisation. Of those, 78 (27%) had ACLF. Short-term mortality was assessed 90 days after inclusion.ResultsAlthough serum concentrations of MIF and sCD74 did not correlate with liver function parameters or ACLF, higher MIF (optimum cut-off >2.3 ng/ml) and lower concentrations of sCD74 (optimum cut-off <66.5 ng/ml) both indicated poorer 90-day transplant-free survival in univariate analyses (unadjusted hazard ratio [HR] 2.01 [1.26–3.22]; p = 0.004 for MIF; HR 0.59 [0.38–0.92]; p = 0.02 for sCD74) and after adjustment in multivariable models. Higher MIF concentrations correlated with surrogates of systemic inflammation (white blood cells, p = 0.005; C-reactive protein, p = 0.05) and were independent of genetic MIF promoter polymorphisms. Assessment of MIF plasma concentrations in portal venous blood and matched blood samples from the right atrium in a second cohort of patients undergoing transjugular intrahepatic portosystemic shunt insertion revealed a transhepatic MIF gradient with higher concentrations in the right atrial blood.ConclusionsSerum concentrations of MIF and its soluble receptor CD74 predict 90-day transplant-free survival in patients with acute decompensation of cirrhosis. This effect was independent of liver function and genetic predispositions, but rather reflected systemic inflammation. Therefore, MIF and sCD74 represent promising prognostic markers beyond classical scoring systems in patients at risk of ACLF.Lay summaryInflammatory processes contribute to the increased risk of death in patients with cirrhosis and ascites. We show that patients with high serum levels of the inflammatory cytokine macrophage migration inhibitory factor (MIF) alongside low levels of its binding receptor sCD74 in blood indicate an increased mortality risk in patients with ascites. The cirrhotic liver is a relevant source of elevated circulating MIF levels.

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.

Association of the macrophage migration inhibitory factor promoter polymorphisms with benign lymphoepithelial lesion of lacrimal gland.

To identify the association of the macrophage migration inhibitory factor (MIF) gene polymorphism with the susceptibility of benign lymphoepithelial lesions (BLEL) of the lacrimal gland. A total of 40 BLEL of lacrimal gland cases were matched with 40 healthy subjects (HS). Extraction the plasma and whole blood DNA of patients of lacrimal gland BLEL and HS. Elisa and polymerase chain reaction was used to determine in plasma contents of MIF and MIF gene SNP-173G>C and STR -794 CATT(5-8) polymorphism, respectively. The MIF levels in plasma were significantly higher in patients with lacrimal gland BLEL versus HS (P<0.001). The -173 G>C MIF polymorphism was significantly associated with lacrimal gland BLEL, with a significantly higher frequency of the C allele in lacrimal gland BLEL patients compared with HS (OR=2.38, 95% CI=1.07-5.31, P=0.032), and the -173 C/x is more frequent in patients than in HS, P=0.037. Besides, we found that the carriage rate of the MIF -173C/x is associated with higher plasma levels of MIF in the BLEL of lacrimal gland. MIF -173G/C variants play an insidious role in susceptibility of BLEL of lacrimal gland. Otherwise, there is no statistically significant correlation exists between MIF-794 CATT (5-8) and BLEL of lacrimal gland.

Macrophage migration inhibitory factor promoter polymorphisms (\u2212794 CATT5\u20138): Relationship with soluble MIF levels in coronary atherosclerotic disease subjects

BackgroundWe analyzed the relationship of −794 CATT5–8 MIF polymorphisms with soluble MIF in Coronary Atherosclerotic Disease (CAD) patients.MethodsA total of 256 patients selected, on which 186 normal-coronary and 70 Coronary artery disease subjects, were recruited in the study (Retrospectively registered). Genotyping of −794 CATT5–8 polymorphisms were performed by PCR and DNA sequencing. Serum MIF levels were measured using an ELISA kit. Patients were classified by coronary angiogram, and CAD based on Gensini’s integral degree (angiographic scoring system).ResultsThe allele frequency and genotype frequency of −794 CATT5–8 did not show any differences in normal-coronary subjects and CAD subjects. In CAD patients, serum MIF levels was lower in CATT (5) subjects than in CATT (7) subjects, while the genotype of −794 CATT5–8 did not show differences in serum MIF levels. In addition, we found a decrease in serum MIF levels in carriers of the (5/5) genotypes the −794 CATT5–8 MIF polymorphisms, although it was not significant. There was no relationship of CAD class and the allele frequency of −794 CATT5–8.ConclusionsThis study found no association between CAD class and −794 CATT5–8 MIF polymorphisms with soluble MIF levels in CAD Subjects.Trial registrationNCT01750502 (November 2012, Retrospectively registered).

Macrophage migration inhibitory factor promoter polymorphisms (-794CATT5-7 ) as potential biomarker for early-stage cervical cancer.

The objective was to investigate the correlation between macrophage migration inhibitory factor (MIF) promoter polymorphisms (-794CATT5-7 ) and early-stage cervical cancer (ESCC) and to identify a potential biomarker for ESCC. A hospital-based case-control study was performed. The case group contained 250 patients with histologically confirmed ESCC. The control group included 147 healthy women. Polymerase chain reaction-single strand conformation polymorphism was used to genotype polymorphisms of MIF promoter -794CATT5-7 . Enzyme-linked immunosorbent assay was applied to detect serum concentration of MIF. The genotype distribution and allele frequency of MIF-794CATT in the ESCC group were significantly different from those in the control group (P<0.05). The 7-CATT repeat carriers were significantly higher in the ESCC group than those in the control group (P<0.05). The 7-CATT repeat carriers (5/7, 6/7, and 7/7) were associated with ESCC and increased risks of cervical cancer (odds ratio=3.5, 3.0, and 5.6; 95% confidence interval=1.2-10.5, 1.2-7.9, and 1.3-25.3, respectively). Serum concentration of MIF was significantly higher in the ESCC group than in the control group (P<0.05), and it was significantly higher in 7-CATT carriers than in non-7-CATT carriers (P<0.05). Neither polymorphisms of MIF-794 nor serum MIF were associated with lymph node metastases and differentiation (P>0.05). MIF promoter polymorphisms (-794CATT) were correlated with ESCC; and 7-CATT might play a role in ESCC. It could be a potential biomarker for ESCC.

Macrophage migration inhibitory factor promoter polymorphisms (-794 CATT 5-8 and -173 G>C): relationship with mRNA expression and soluble MIF levels in young obese subjects.

We analyzed the relationship of −794 CATT5–8 and −173 G>C MIF polymorphisms with mRNA and soluble MIF in young obese subjects. A total of 250 young subjects, 150 normal-weight and 100 obese subjects, were recruited in the study. Genotyping of −794 CATT5–8 and −173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP, respectively. MIF mRNA expression was determined by real-time PCR and serum MIF levels were measured using an ELISA kit. For both MIF promoter polymorphisms, no significant differences in the genotype and allele frequencies between groups were observed. MIF mRNA expression was slightly higher in obese subjects than in normal-weight subjects (1.38-fold), while soluble MIF levels did not show differences between groups. In addition, we found an increase in MIF mRNA expression in carriers of the 6,6 and C/C genotypes and the 6G haplotype of the −794 CATT5–8 and −173 G>C MIF polymorphisms, although it was not significant. In conclusion, this study found no relationship between obesity and MIF gene promoter polymorphisms with MIF mRNA expression in young obese subjects.

A functional microsatellite in the macrophage migration inhibitory factor gene influences susceptibility to meningococcal sepsis

The cytokine migration inhibitory factor (MIF) has recently emerged as an important effector molecule of innate immune responses and sepsis. Two functional MIF promoter polymorphisms, a 5–8 CATT tetranucleotide repeat at -794 (CATT5–8) and a -173*G/C single nucleotide polymorphism, have been associated with susceptibility to and/or severity of rheumatoid arthritis, atopy and ulcerative colitis. Our objective was to study the impact of MIF gene polymorphisms on susceptibility to Neisseria meningitidis sepsis and to analyze the functional and biological effects of MIF polymorphisms in vitro.

Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma

To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc). Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups. The frequency of the -173*C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173*C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype. Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc.

In This Issue

If the genetics of complex diseases is going to produce therapeutic advance, psoriasis is perhaps the best place to start. Psoriasis has one of the highest heritabilities of any common inflammatory disease and, just to make the decision easier, we have astonishingly little insight into key environmental determinants. Unlike, say, atopy, where marked secular changes have reportedly occurred, psoriasis epidemiology seems remarkably boring and uniform. Over the last several years, there has been an epidemic of allelic association studies published for many diseases, many in the Journal, and yet, armchair enthusiasts will notice that they have often been beset my methodological problems. All too often they have been less than statistically robust, and the magnitude of the effect size, smaller than the author's, and more importantly, the readers would wish for. Donn and colleagues in this issue report a positive association between macrophage migration inhibitory factor promoter polymorphisms and psoriasis. The magnitude of the odds ratio is, again, small (∼1.5–1.7), but in the authors' favor they have functional evidence that the promoter polymorphism studies are functionally significant, and that the amounts of their gene product are altered in psoriasis. Which way is the field going and how does this paper help? First, once we exclude human leucocyte antogen (HLA) effects, we have lost perhaps half of the heritability of psoriasis. Researchers are left trying to apportion this remaining variability between an ever-increasing range of loci. Second, and here is a paradox, we feel happier with associations we can predicate on a mechanistic model (in the case of this study, what was known about this cytokine), but what we want the genetics to do is to point us in the direction of pathways we did not know about. Otherwise, reverse genetics has become synonymous with biochemistry, losing some of its ability to offer magical insights along the way. Given that disease-state prediction is not critical, then this all means that either we have to get used to betting on weak evidence or cast around for some new insights.