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The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia

Sachin Yende^*, Derek C. Angus^*,1, Lan Kong^*,, John A. Kellum^*, Lisa Weissfeld^*,, Robert Ferrell, David Finegold, Melinda Carter^*, Lin Leng, Zhi-Yong Peng^* and Richard Bucala

^* The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;

Department of Biostatistics and

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA; and

Department of Medicine, and Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

¹ Correspondence: Department of Critical Care Medicine, 614 Scaife Hall, 3550 Terrace St., University of Pittsburgh, Pittsburgh, PA 15261, USA. E-mail: angusdc{at}upmc.edu

The cytokine, macrophage migration inhibitory factor (MIF), is encoded in a functionally polymorphic locus and subjects with high-expression MIF alleles are at an increased risk of inflammatory disease. Severe sepsis is the leading cause of death in intensive care units, and the prevailing hypothesis is that an excessive innate response contributes to its pathogenesis. To assess if MIF alleles influence the clinical course of infection, we conducted a case-control study to assess susceptibility and a parallel inception cohort study of community-acquired pneumonia (CAP) to assess risk of severe sepsis and 90-d mortality. Two distinct polymorphisms in the MIF promoter were analyzed: a G/C transition at –173 and a CATT repeat at –794. The frequency of both polymorphisms was similar in the CAP cohort (n=1739) and controls (n=639); however, the 90-d mortality was lower for the high-expression C allele (P=0.003). This association remained significant after adjusting for demographics, comorbid conditions, and disease severity score [hazard ratio=0.64 (0.44–0.91), P=0.01]. The hazard ratio was similar in different geographic subcohorts, and the association remained significant after adjusting for false discovery. These data indicate that polymorphisms associated with higher MIF expression may have a beneficial effect in community-acquired pneumonia.—Yende, S., Angus, D. C., Kong, L., Kellum, J. A., Weissfeld, L., Ferrell, R., Finegold, D., Carter, M., Leng, L., Peng, Z.-Y., Bucala, R. The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired pneumonia.

Key Words: cytokines • innate immunity • sepsis • TNF

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