The macrophage migration inhibitory factor (MIF) –173G/C promoter polymorphism influences upper gastrointestinal tract involvement and disease activity in patients with Crohn's disease

Objectives: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with increased expression in inflammatory bowel disease. Aims: To analyze the role of the MIF –173G/C single nucleotide polymorphism in Crohn's disease (CD). Methods: Using restriction fragment length polymorphism analysis, genomic DNA of 198 patients with CD and of 159 unrelated controls was analyzed for the –173G/C SNP in the MIF promoter region. Colonic MIF mRNA expression was measured by quantitative PCR, serum MIF levels by ELISA. Results: Thirty-six of the 146 G/G wildtype carriers (24.7%), but only three of the 45 G/C heterozygotes (6.7%) and only one of the C/C homozygotes (14.3%) were diagnosed of upper gastrointestinal tract involvement (p=0.009, OR=0.22, 95% CI 0.06–0.75 for wildtype vs. hetero- and homozygous carriers). This result was confirmed in a second prospective study, in which all patients diagnosed of upper gastrointestinal involvement (n=13) were G/G wildtype carriers (p=0.01 vs. controls). All patients (n=12; 100%) with a CDAI >300 were G/G wildtype carriers compared to only 65.6% wildtype carriers in the group with a CDAI <150 (p=0.016). MIF is expressed in the colonic mucosa of CD patients and intestinal epithelial cells but its mRNA expression does not correlate with the degree of inflammation and is not up-regulated by proinflammatory cytokines. In CD, MIF serum levels are not influenced by the MIF –173G/C polymorphism. Conclusions: The MIF –173G/C polymorphism appears to be a factor contributing to a particular CD phenotype characterized by protection against upper gastrointestinal tract involvement and severe disease activity.