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The influence of macrophage migration inhibitory factor gene polymorphisms on outcome from community-acquired
Sachin Yende1, Derek C Angus, Lan Kong
1Clinical Research, Investigation, and Systems Modeling of Acute Illness Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Abstract:
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.
Insights
High-expression macrophage migration inhibitory factor (MIF) alleles, previously linked to inflammatory disease, were associated with lower 90-day mortality in community-acquired pneumonia patients. This suggests a protective role for certain MIF polymorphisms in severe infection outcomes.
Area of Science:
- Immunogenetics
- Infectious Diseases
- Critical Care Medicine
Background:
- Macrophage migration inhibitory factor (MIF) is a key cytokine in innate immunity, encoded by a polymorphic locus.
- High-expression MIF alleles are generally associated with increased risk of inflammatory diseases.
- Severe sepsis, a major cause of intensive care unit mortality, is hypothesized to involve an excessive innate immune response.
Purpose of the Study:
- To investigate the influence of macrophage migration inhibitory factor (MIF) gene polymorphisms on the clinical course of infection.
- To assess susceptibility to severe sepsis and 90-day mortality in community-acquired pneumonia (CAP) patients based on MIF alleles.
Main Methods:
- A case-control study for susceptibility and an inception cohort study for severe sepsis and mortality in community-acquired pneumonia (CAP) patients.
- Analysis of two distinct MIF promoter polymorphisms: G/C transition at -173 and CATT repeat at -794.
- Statistical analysis adjusted for demographics, comorbid conditions, disease severity, and false discovery.
Main Results:
- Frequencies of analyzed MIF polymorphisms were similar between CAP patients (n=1739) and controls (n=639).
- A significantly lower 90-day mortality was observed in patients with the high-expression C allele (P=0.003).
- This association remained statistically significant after comprehensive adjustments (hazard ratio=0.64, P=0.01).
Conclusions:
- Polymorphisms in the macrophage migration inhibitory factor (MIF) gene associated with higher expression may confer a beneficial effect in community-acquired pneumonia.
- These findings suggest a complex, potentially protective role for specific MIF alleles in the context of severe bacterial infections.
