Macrophage Migration Inhibitory Factor Gene Polymorphisms Research Articles

Haplotypes association of [-794(CATT)5-8/-173G>C] MIF gene polymorphism with Acute Coronary Syndrome

Event Abstract Back to Event Haplotypes association of [-794(CATT)5-8/-173G>C] MIF gene polymorphism with Acute Coronary Syndrome Emmanuel V. Alvarado1, José F. Muñoz-Valle2, Elena Sandoval Pinto1, Ilian Janet G. González1, Angélica V. Haro1 and Jorge Ramón P. Gutierrez2* 1 Estudiante de doctorado, Mexico 2 Universidad de Guadalajara, Mexico Introduction: Acute coronary syndrome (ACS) is characterized by acute, regional reductions in coronary blood flow and myocardial ischemia. ACS describes a spectrum of clinical manifestations, including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). The vast majority of ACS are triggered by disruption of an atherosclerotic plaque. The macrophage migration inhibitory factor (MIF) is related to the progression of atherosclerosis, which, in turn, is a key factor in the development of acute coronary syndrome (ACS). MIF has a single nucleotide polymorphism at position -173 G>C and a CATT short tandem repeat (STR) at position -794 that might be involved in its expression rate. The aim of this study was to investigate the association of the haplotypes [-794(CATT)5-8/-173G>C] of MIF gene polymorphism with ACS in a western Mexican population. Methods: This research included 200 ACS patients classified according to the criteria of the American College of Cardiology (ACC) and 200 healthy subjects (HS). The -794 (CATT)5-8 MIF gene polymorphism was analyzed using a conventional polymerase chain reaction (PCR) technique and The -173 G>C MIF polymorphism was genotyped by the PCR restriction fragment length polymorphism (RFLP) technique. The Hardy-Weinberg equilibriumtest and genotype and allele frequencies were calculated by the chi-square test or Fisher’s exact test, when applicable.Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to test the probability that the genotype and allele frequencies were associated with ACS. A □□ value <0.05 was considered to be statistically significant. All the statistical analyses were done with the Stata 9.0 software. Results: The haplotype 6G was the most frequent in both groups (ACS: 51% and HS: 47%). A significant association was found between the 7G haplotype and susceptibility to ACS (3% vs 6% in ACS and HS respectively, p = 0.04). Conclusion: We conclude that the 7G haplotype of the MIF gene polymorphism is associated with susceptibility to ACS in a Western Mexican population. Acknowledgements The authors greatly appreciate the participation of every person in this study Keywords: ACS, Atherosclerosis / CAD, MIF, MIF HAPLOTYPES, Cardiovascular Diseases Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Oral Presentation Topic: Immunotherapy Citation: Alvarado EV, Muñoz-Valle JF, Sandoval Pinto E, González IG, Haro AV and Gutierrez JP (2015). Haplotypes association of [-794(CATT)5-8/-173G>C] MIF gene polymorphism with Acute Coronary Syndrome. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00320 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 May 2015; Published Online: 15 Sep 2015. * Correspondence: Dr. Jorge Ramón P Gutierrez, Universidad de Guadalajara, Guadalajara Jalisco, Mexico, imey_99@yahoo.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Emmanuel V Alvarado José F Muñoz-Valle Elena Sandoval Pinto Ilian Janet G González Angélica V Haro Jorge Ramón P Gutierrez Google Emmanuel V Alvarado José F Muñoz-Valle Elena Sandoval Pinto Ilian Janet G González Angélica V Haro Jorge Ramón P Gutierrez Google Scholar Emmanuel V Alvarado José F Muñoz-Valle Elena Sandoval Pinto Ilian Janet G González Angélica V Haro Jorge Ramón P Gutierrez PubMed Emmanuel V Alvarado José F Muñoz-Valle Elena Sandoval Pinto Ilian Janet G González Angélica V Haro Jorge Ramón P Gutierrez Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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Association Between Genetic Polymorphism of the MIF Gene and Colorectal Cancer in Taiwan.

Colorectal cancer (CRC) is the highest leading cause of cancer-related mortality in Taiwan. Macrophage migration inhibitory factor (MIF) has recently been defined as a novel protumorigenic factor that promotes cell proliferation, migration, and invasion. The aim of the present study is to identify the association between MIF gene polymorphism and CRC. A case-control study was designed to test the hypothesis. A total of 192 biopsy-diagnosed CRC patients (CRC) and 256 healthy subjects (control) were recruited. Genotyping of four single nucleotide polymorphism (SNPs; rs755662, rs11548059, rs1049829, rs1803976) at chromosome positions 755662 (5' UTR), 11548059 (exon2), 1049829 (exon2), 1803976 (exon3) was performed using a Taqman SNP genotyping assay. There is a significant difference in genotype frequency distribution of rs755662 polymorphism between CRC patients and controls (P = 0.011). No significant difference was found in the frequency distribution of rs11548059, rs1049829, rs1803976 polymorphism in CRC patients and controls (P = 0.660, P = 0.700, and P = 0.959, respectively). Moreover, the MIF-173 SNP was also significantly associated with young patients (age < 50 years, P = 0.026) late stage (Stage IV, P = 0.038) and poor differentiation group (P = 0.040). Compared to the control group, the MIF-173 SNP also significantly associated with patients with stages III and IV (P = 0.034 and 0.003, respectively). The presence of MIF-173 (G/C) gene polymorphism (rs755662) was associated with susceptibility, patient age, and stages of CRC in Taiwanese.

Macrophage migration inhibitory factor: Association of −794 CATT5–8 and −173 G>C polymorphisms with TNF-α in systemic lupus erythematosus

Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive feedback loop with TNF-α that could perpetuate the inflammatory process in systemic lupus erythematosus (SLE). In this case–control study we investigated whether commonly occurring functional MIF polymorphisms are associated with SLE as well as with MIF and TNF-α serum levels in a Mexican-Mestizo population. Genotyping of the −794 CATT5–8 (rs5844572) and −173 G>C (rs755622) MIF polymorphisms was performed by PCR and PCR–RFLP, respectively in 186 SLE patients and 200 healthy subjects. MIF and TNF-α serum levels were determined by ELISA. A significant increase of MIF and TNF-α levels was found in SLE patients. According to a genetic model, we found a significant association of genotypes carrying the −794 CATT7 and −173∗C risk alleles with susceptibility to SLE and with a significant increase of TNF-α. In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population.

Association between MIF gene variation and Meniere's disease

Several pieces of evidence support the involvement of immune system in Menière's disease (MD). Macrophage migration inhibitory factor (MIF) plays a key role in immune-mediated reactions. Several studies have shown an association between MIF gene polymorphisms and susceptibility to various inflammatory and autoimmune disorders. The aim of this study was to explore the association between MIF-173 G/C polymorphism and MD in an Iranian population. In this case-control association study, MD cases (N=72) were recruited and were comprised of definitive MD (N=58) and probable MD (N=14) subjects. Normal healthy subjects (N=100) were also included. Genotyping for MIF-173 G/C polymorphism was carried out using PCR-RFLP technique. There was a significant increase in genotype GG in patients with MD compared with the control group. (GG vs. GC+CC, P=0.02, OR=2.08, 95% CI: 1.02-4.3). This was more significant when definitive MD was stratified and compared with the controls (GG vs. GC+CC, P=0.009, OR=2.6, 95% CI=1.19-6.18). This study's result indicates the potential role of MIF in MD of which further evaluation is required. Also, the more significant association between MIF gene polymorphism and definitive MD designates the involvement of specific pathogenic mechanisms which may be considered as a marker for diagnosis.

Association between MIF gene polymorphisms and carotid artery atherosclerosis

Atherosclerosis is a chronic inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Polymorphisms including five- to eight-repeat CATT variants ((CATT)5–8) and G-173C in the promoter region of the MIF gene are associated with altered levels of MIF gene transcription. The purpose of the study is to investigate the relationship between promoter polymorphisms of the MIF gene and the severity of carotid artery atherosclerosis (CAA). The severity of CAA was assessed in 593 individuals with a history of ischemic stroke by using sonographic examination, and the MIF promoter polymorphisms of these individuals were genotyped. The carriage of (CATT)7 (compared to genotypes composed of (CATT)5, (CATT)6, or both), carriage of C allele (compared to GG), and carriage of the haplotype (CATT)7-C (compared to genotypes composed of (CATT)5-G, (CATT)6-G, or both) were significantly associated with an increase in the severity of CAA. We conclude that polymorphisms in the MIF gene promoter are associated with CAA severity in ischemic stroke patients. These genetic variants may serve as markers for individual susceptibility to CAA.

Role of MIF gene polymorphisms in systemic lupus erythematosus and prospects for therapeutic intervention

The cytokine macrophage migration inhibitory factor (MIF) counter-regulates the immunosuppressive action of glucocorticoids and inhibits activation-induced apoptosis. MIF is encoded in a polymorphic locus with a variant allele frequency >5% and high-expression alleles are associated with clinical severity of rheumatoid arthritis, scleroderma, and asthma but improved outcome from pneumonia. We completed a candidate gene association study in SLE (3195 patients and controls) to examine the relationship between two promoter polymorphisms in MIF: a -794 CATT5-8 microsatellite repeat (rs5844572), where increased repeat number leads to greater MIF expression; and a -173 G/C SNP (rs755622) that is in linkage disequilibrium with CATT7. Patients with the high-expression CATT7 allele had lower SLE incidence: OR = 0.63, P = 0.001 in Caucasians and OR = 0.46, P = 0.012 in African-Americans. Among patients with established SLE, those with serositis, nephritis, and cerebritis had reduced frequencies of low-expression MIF genotypes (CATT5) when compared with patients without end-organ involvement (P = 0.005 for serositis, P = 0.023 for nephritis, and P = 0.04 for cerebritis). Plasma MIF levels and TLR4, TLR7, and TLR9 stimulated MIF production reflected the underlying MIF genotype of the studied groups. These data suggest that MIF exerts a dual influence on the immunopathogenesis of SLE. High-expression MIF genotypes are associated with a reduced susceptibility to SLE, perhaps by contributing to enhanced clearance of infectious agents. Once SLE develops, however, low-expression MIF genotypes may protect from ensuing inflammatory end-organ damage [1]. We also examined the therapeutic impact of MIF antagonism in two mouse models of spontaneous SLE. In both the NZB/NZW F1 and the MRL/lpr mouse strains, anti-MIF or small molecule MIF receptor antagonism reduced functional and histological indices of glomerulonephritis, MIF-R+ leukocyte recruitment, and proinflammatory cytokine and chemokine expression [2]. A humanized anti-MIF developed from our studies has recently entered phase I clinical testing [3]. These data highlight the importance of MIF in the development of autoimmunity and support the potential clinical feasibility of pharmacologic MIF antagonism. We anticipate that MIF antagonists may be most effectively applied in those individuals who, on the basis of their genotype, manifest a MIF-dependent form of autoimmunity.

Association of tuberculosis and polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) in a Southwestern China Han population

The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of immune diseases. High levels of MIF have been detected in the sera of patients with tuberculosis (TB), and it has been proposed that MIF gene polymorphisms may influence the risk of developing TB. The aim of this study was to evaluate the potential relationship between functional polymorphisms of MIF and TB in a Han population from Southwestern China. TB patients (n=215) and healthy unrelated controls (n=245) were recruited for this study. Genomic DNA was isolated from all the participants. The MIF-173 G/C SNP was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The MIF-794 CATT5–8 microsatellite was evaluated by direct sequencing of the subsequent PCR products. Association analysis of the two polymorphisms showed that the frequency of -173 (GC+CC) in TB patients and controls was 49.3% and 31.4%, respectively, which was statistically significant (OR=2.12, 95% CI=1.45–3.10, P<0.001); the frequencies of -794 (7/X+8/X) were 56.7% and 45.3%, respectively, also statistically significant between the TB and healthy controls (OR=1.58, 95% CI=1.10–2.29, P=0.015). In summary, Genetic variation in the MIF gene is closely associated with tuberculosis. Both the 173 (GC+CC) SNP and -794 (7/X+8/X) microsatellite increased the risk of Chinese Han developing TB.

Mannose Binding Lectin and Macrophage Migration Inhibitory Factor Gene Polymorphisms in Turkish Children with Cardiomyopathy: No Association with MBL2 Codon 54 A/B Genotype, but an Association between MIF -173 CC Genotype

Myocardial inflammation is one of the commonest mechanisms in cardiomyopathy (CMP). Mannose binding lectin (MBL) is a key molecule in innate immunity, while macrophage migration inhibitory factor (MIF) is a constitutive element of the host defenses. We investigated the possible association between polymorphisms of MBL2 and MIF genes and CMP in Turkish children. Twenty-children with CMP and 30 healthy controls were analyzed for codon 54 A/B polymorphism in MBL, and -173 G/C polymorphism in MIF genes by using PCR-RFLP methods. No significant difference was found between genotypes and alleles of MBL2 gene codon 54 A/B polymorphism in patients and controls (p>0.05). However, serum uric acid levels was found higher in dilated CMP patients with AA genotype. Frequency of MIF -173 CC genotype was significantly higher in patients (p<0.05), and sodium levels were higher in patients with MIF -173 CC genotype. This study is the first to investigate the MBL and MIF gene polymorphisms in Turkish children with CMP. We conclude that CC genotype of MIF (-173) polymorphism may be a risk factor for CMP patients. However, further studies with larger samples are needed to address the exact role of this polymorphism in CMP.

A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease

Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms (-794 CATT(5-8) microsatellite and -173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT(5) allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001), which increased in correlation with the CATT(5) copy number (P=0.04). The CATT(5) allele, but not the -173 G/C alleles, was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2-6.4), P=0.02]. A family-based association test (i.e., transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT(5) was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP-1 monocytic cells or in a whole-blood assay, CATT(5) was found to be a low-expression MIF allele (P=0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together, these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence, severity, and outcome of meningococcal disease in children.

Contribution of the -173 G/C Polymorphism of Macrophage Migration Inhibitory Factor Gene to the Risk of Inflammatory Bowel Diseases

Inflammatory bowel disease (IBD) represents a heterogeneous group of chronic disorders characterized by inflammation of gastrointestinal tract, typically with a relapsing and remitting clinical course of unknown etiology. Presumably, IBD develops with response exogenous environmental factors only in persons with genetic predisposition. This predisposition was suggested to be associated with polymorphism and mutations in genes encoding proinflammatory immune system proteins. Enhanced production of macrophage migration inhibitory factor (MIF) was found in patients with inflammatory bowel disease (IBD) and mice with experimental colitis. These results suggest that MIF plays a critical role in etiology of the colitis.The aim of the study was determine whether the MIF -173 G/C gene polymorphism is associated with the susceptibility to inflammatory bowel disease (IBD). A total of 99 IBD patients, including 58 patients with ulcerative colitis (UC) and 41 with Crohn's disease (CD) and 436 healthy controls recruited from the Polish population, were genotyped for MIF polymorphisms. Genotyping of MIF gene polymorphism was performed by a RFLP-PCR. We found an increased risk of UC for the C allele of the MIF-173 G/C polymorphism. The distribution of the genotypes was not significantly different in the CD group compared with the controls. We demonstrated that the C allele is associated with an increased risk for development of UC. This suggests that the G/C polymorphism in the MIF gene promoter may be a potential risk factor for UC in Polish population.

Analysis of MIF, FCGR2A and FCGR3A gene polymorphisms with susceptibility to pulmonary tuberculosis in Moroccan population

In order to investigate the influence of functional polymorphisms of macrophage migration inhibitory factor (MIF), Fcg receptors CD16A (FCGR3A) and CD32A (FCGR2A) genes on susceptibility to pulmonary tuberculosis (PTB) in the Moroccan population, we analyzed 123 patients with PTB and 154 healthy controls. The genotyping for MIF-173 (G/C) (rs755622), FCGR2A-131H/R (rs1801274) and FCGR3A-158V/F (rs396991) was carried out using TaqMan SNP Genotyping Assay method. We found a statistically significant increase of the MIF -173CC homozygote genotype and MIF -173*C allele frequencies in PTB patients compared with healthy controls (17.07%versus 5.84%, P = 0.003; and 35.37%versus 26.30%, P = 0.02; respectively). In contrast, no association was observed between FCGR2A-131H/R and FCGR3A-158V/F polymorphisms and tuberculosis disease. Our finding suggests that MIF -173*C variant may play an important role in the development of active tuberculosis.

Association of proinflammatory cytokines with end stage renal disease

Cytokines play an important role in the pathogenesis of kidney disease and its progression to ESRD. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is released by macrophages and lymphocytes and interferon-gamma (IFN-gamma) plays an important pathogenetic role in several inflammatory diseases. We have explored the role of MIF -173 G/C, INF-gamma +874 A/T and INF-gamma CA repeat microsatellite gene polymorphisms as a susceptibility for ESRD. We genotyped MIF and IFN-gamma gene polymorphisms in 258 patients with ESRD and 569 healthy controls free of any renal disease using PCR-RFLP, gene sequencing and gene scanning methods. The frequency of high producer MIF -173 CC genotype was higher (10.1%) in ESRD than in controls (1.2%) (p=0.0001, OR=8.9; 95%CI=3.8-21.0). It was observed that there was significant differences in the genotype frequencies of the IFN-gamma +874 A/T at genotypic as well as at allelic level (p=0.0023 and p=0.001) among patients and controls. A significant difference was found in the frequency distribution between the two groups at IFN-gamma CA microsatellite polymorphism (p=0.0001) (CA(17))/(CA(17)). Combined analysis revealed a higher risk ( approximately 9-fold) in ESRD patients with high MIF -173 G/C and high INF-gamma +874 A/T protein producing phenotypes. These results highlight the role of MIF and IFN-gamma in ESRD disease.

Association of Macrophage Migration Inhibitory Factor Gene Promoter Polymorphisms with Multiple Sclerosis in Turkish Patients

Elevated levels of macrophage migration inhibitory factor (MIF) have been observed in the cerebrospinal fluid of patients with multiple sclerosis. This study was designed to determine if MIF gene polymorphisms are associated with multiple sclerosis and disease severity. In total, 120 relapsing-remitting patients with multiple sclerosis and 120 control subjects were enrolled in the study. There was a statistically significant increase in the MIF -173 CC genotype in patients with multiple sclerosis compared with the control subjects. The MIF -794 6/7 genotype had a significantly lower progression index compared with MIF -794 6/6. Patients with the MIF -173 CC genotype had a significantly lower age of disease onset compared with those with the MIF -173 CG and MIF -173 GG genotypes. Additionally, patients with the MIF -794 5/6 genotype had a significantly later age of disease onset. This study indicates that the MIF -173 CC genotype may cause susceptibility to multiple sclerosis in the white Turkish population and a younger age of disease onset is associated with this polymorphism.

Inflammatory cytokine gene polymorphisms increase the risk of atrophic gastritis and intestinal metaplasia

To investigate the effects of interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF) gene polymorphisms, Helicobacter pylori (H. pylori) infection, on the risk of developing severe chronic atrophic gastritis (SCAG) and intestinal metaplasia (IM). A total of 372 cases were selected from a cohort study in Linqu County, a high risk area for gastric cancer (GC) in northern China. To obtain a sufficient group size, patients with normal or superficial gastritis were included. Based on an average follow-up period of 56 mo, the 372 cases were divided into no progression group (no histological progression from normal or superficial gastritis, n = 137), group I (progressed from normal or superficial gastritis to SCAG, n = 134) and group II (progressed from normal or superficial gastritis to IM, n = 101). IL-8, MIF gene polymorphisms were detected by polymerase chain reaction-based denaturing high-performance liquid chromatography analysis and DNA sequencing. An increased risk of SCAG was found in subjects with IL-8-251 AA genotype [odds ratio (OR) = 2.62, 95% CI: 1.23-5.72] or IL-8-251 A allele carriers (AA + AT) (OR = 1.81, 95% CI: 1.06-3.09). An elevated risk of IM was found in subjects with IL-8-251 AT genotype (OR = 2.27, 95% CI: 1.25-4.14) or IL-8-251 A allele carriers (OR = 2.07, 95% CI: 1.16-3.69). An increased risk of SCAG was found in subjects with MIF-173 GC genotype (OR = 2.36, 95% CI: 1.38-4.02) or MIF-173 C allele carriers (GC + CC) (OR = 2.07, 95% CI: 1.21-3.55). An elevated risk of IM was found in subjects with MIF-173 CC genotype (OR = 2.27, 95% CI: 1.16-4.46) or MIF-173 C allele carriers (OR = 3.84, 95% CI: 1.58-9.34). The risk of SCAG and IM was more evident in subjects carrying IL-8-251 A allele (OR = 6.70, 95% CI: 1.29-9.78) or MIF-173 C allele (OR = 6.54, 95% CI: 2.97-14.20) and positive for H. pylori infection. IL-8-251 and MIF-173 gene polymorphisms are significantly associated with the risk of SCAG and IM in a population with a high risk of GC in Linqu County, Shandong Province, China.

The macrophage migration inhibitory factor ( MIF) gene polymorphism in Czech and Russian patients with myocardial infarction

Background Macrophage migration inhibitory factor (MIF) is a cytokine implicated in early and advanced atherosclerosis. The aim of this study was to investigate whether polymorphism of MIF gene is associated with myocardial infarction (MI). Methods Single nucleotide polymorphism (SNP) in MIF gene (− 173G/C, rs755622) was investigated in Czech ( n = 219) and Russian ( n = 240) MI patients and population control from the same geographical areas (Czech, n = 137; Russian, n = 174). Further, another SNP (rs1007888) located within the 3' flanking region of the MIF gene was investigated in Czech MI patients and control subjects. Results There were no significant differences in the distribution of MIF − 173G/C genotypes, alleles or carriage rates between case and control groups in either populations. However, the GG genotype of the MIF SNP rs1007888 was associated with MI in Czech female patients ( p = 0.027). Conclusions Taken together with previous reports, our study suggests that particular MIF gene polymorphisms may contribute to MI susceptibility in females.

Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations

The macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine central to the response to endotoxemia, is a putative biomarker in acute lung injury (ALI). To explore MIF as a molecular target and candidate gene in ALI, the MIF gene and protein expression were examined in murine and canine models of ALI (high tidal volume mechanical ventilation, endotoxin exposure) and in patients with either sepsis or sepsis-induced ALI. MIF gene expression and protein levels were significantly increased in each ALI model, with serum MIF levels significantly higher in patients with either sepsis or ALI compared with healthy controls (African- and European-descent). The association of 8 MIF gene polymorphisms (single-nucleotide polymorphisms (SNPs)) (within a 9.7-kb interval on chromosome 22q11.23) with the development of sepsis and ALI in European-descent and African-descent populations was studied next. Genotyping in 506 DNA samples (sepsis patients, sepsis-associated ALI patients, and healthy controls) revealed haplotypes located in the 3' end of the MIF gene, but not individual SNPs, associated with sepsis and ALI in both populations. These data, generated via functional genomic and genetic approaches, suggest that MIF is a relevant molecular target in ALI.

The Role of Macrophage Migration Inhibitory Factor (MIF) Genetic Polymorphisms in Predicting the Development of Macrocytic Anemia in HIV+ Patients.

Anemia is the most common hematologic morbidity in HIV+ patients and is associated with increased mortality. In previous studies, we have examined anemia-associated mortality in over 30,000 HIV+ men cared for within the VA system, and have confirmed the increased mortality previously shown to be associated with anemia. Most strikingly, however, we have demonstrated that macrocytosis in particular is an independent risk factor for early mortality even after correcting for alcohol abuse, liver disease, or therapy with AZT. We hypothesize that macrocytosis reflects a proinflammatory state associated with HIV and magnified by co-morbidities. We have therefore sought to link anemia with known markers of underlying inflammation. Genetic variants that affect the level of cytokine gene expression have been shown to influence the development of anemia associated with a variety of illnesses. One such polymorphism occurs in the macrophage migration inhibitory factor (MIF) gene, a cytokine secreted by macrophages and T-cells that induces release of TNF and IL-6 from macrophages. Our group has defined two polymorphisms in the promoter of the human MIF gene that affect the level of MIF expression. The first, a tetranucleotide CATT repeat, occurs 5-8 times within a Pit-1transcription factor binding site, and increased numbers of repeats are associated with higher levels of MIF expression. The second, a single-nucleotide polymorphism (SNP), has been identified at −173 bp (G/C), although its significance in predicting cytokine levels has been hard to separate from the associated CATT repeat polymorphism. High expression MIF polymorphisms have been shown to correlate with the development of anemia in the setting of malaria, to influence recovery from community acquired pneumonia, and to increase the severity of manifestations of rheumatoid arthritis. We therefore undertook to examine whether MIF polymorphisms might influence the development of anemia in the setting of HIV. We wished to test the hypothesis that the presence of high-expressing alleles of MIF predisposes to the development of anemia in the setting of HIV, particularly in association with other co-morbid conditions. In order to address this question, genomic DNA isolated/extracted from blood collected as part of the Veterans Aging Cohort Study (VACS) has been genotyped for the polymorphisms using a PCR based method. These data are being correlated with anemia, mean corpuscular volume, and CD4 count. We are using Cox proportional hazards models stratified by age, race, HIV severity, and co-morbid disease to examine associations between anemia type/severity and MIF gene polymorphisms. We are currently analyzing the prevalence of high-expressing MIF alleles in non-anemic and anemic patients with and without HIV, using multivariate analysis to identify correlations of genotype with markers of morbidity. It is hoped that these studies will provide insight into the etiology of anemia in HIV+ patients in general, and of macrocytic anemia in particular.

Investigating disease susceptibility and the negative correlation of schizophrenia and rheumatoid arthritis focusing on MIF and CD14 gene polymorphisms

Schizophrenia and rheumatoid arthritis (RA) are both chronic diseases with an estimated genetic component of 60%. While RA is a well-known autoimmune inflammatory joint disease, recent data point to an active immune process also being involved in schizophrenia. Several studies confirmed the negative association between schizophrenia and RA, indicating genetic factors that predispose to the one disorder, while protecting from the other. Macrophage migration inhibitory factor (MIF) and the monocytes surface receptor CD14 are involved in the development and maintenance of chronic inflammation. We therefore investigated if the − G173C single nucleotide polymorphism (SNP) and the tetranucleotide repeat CATT (5–8) at position − 794 of the MIF gene and the CD14–C159T transition are candidates for genetic liability to schizophrenia and RA or could explain the negative association between them. In our study 157 schizophrenic patients, 119 patients suffering from RA, and 225 healthy individuals were genotyped. All subjects were Caucasians. The CD14- and MIF-genotypes were equally distributed in all three groups. From our results, we cannot confirm the hypothesis that the investigated genetic mutations within the MIF and/or the CD14 gene are involved in the aetiology of either disease or could explain the negative correlation of schizophrenia and RA.

Positive Association of Macrophage Migration Inhibitory Factor Gene‐173G/C Polymorphism with Biliary Atresia

Macrophage migration inhibitory factor (MIF) is a pleiotrophic lymphocyte and macrophage cytokine; it is likely to play an important role in innate immunity. Its expression was increased in several inflammatory diseases, and MIF gene polymorphisms have an effect on disease outcome and response to glucocorticoid treatment. To investigate the role of the 173G/C polymorphism of the MIF gene for susceptibility to biliary atresia (BA). Between February 2002 and November 2004, 18 patients (mean age 1 +/- 0.4 years) diagnosed as having BA were studied. After informed consent, blood was collected, and DNA was obtained. MIF 173C/G polymorphism was detected using the polymerase chain reaction-restriction fragment length polymorphism based method. BA patients were compared with a group of chronic liver disease patients (CLD) (n = 36) and a group of unrelated healthy controls (n = 103). MIF-173C allele frequency was significantly higher than both the CLD and healthy control groups (P = 0.03, odds ratio [OR] 4.4, 95% confidence interval [CI] 1.3-15.1; P = 0.000, OR 4.1, 95% CI 2.3-7.6, respectively). Univariate analysis showed that MIF-173G/C polymorphism was significantly associated with BA (for GC genotype, OR = 6, 95 % CI 2.8-11.5, P = 0.000). There was no significant correlation between pediatric end stage liver disease score and MIF genotypes both in BA and CLD groups. Our results suggest that the -173C allele of the MIF gene might be associated with the susceptibility to BA.

Polymorphisms of the Macrophage Inhibitory Factor and C-Reactive Protein Genes in Subjects with Alzheimer’s Dementia

Neuroinflammation is a central feature of Alzheimer’s disease (AD). C-reactive protein (CRP) is a key molecule of the acute phase of inflammation that has been localized in the two characteristic lesions of AD brain, senile plaque and neurofibrillary tangles. On the other hand, the macrophage migration inhibitory factor (MIF) is a cytokine with multiple biological activities, including the ability to act as potent amyloid beta (A-beta)-binding protein. Two common polymorphisms have been recently detected in the genes encoding for CRP and MIF and have been associated with significant modifications of plasma levels and activity of the corresponding proteins. Following these observations, we hypothesized that CRP and MIF gene polymorphisms might contribute to the development and progression of neurodegenerative disorders and evaluated their association with AD. CRP and MIF gene polymorphisms were examined by polymerase chain reaction and restriction enzyme analysis in 116 Italian subjects affected by probable AD and 184 age- and sex-matched controls. We did not find a statistically significant difference in the distribution of CRP and MIF genotypes and alleles between AD subjects and controls. Although these data need further confirmation, they indicate that CRP and MIF gene polymorphisms are not associated with AD.