Impact of MIF gene promoter polymorphism on F508del cystic fibrosis patients

Abstract

Macrophage migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine sustaining the acute response to gram-negative bacteria and a regulatory role for MIF in Cystic Fibrosis has been suggested by the presence of a functional, polymorphic, four-nucleotide repeat in this gene's promoter at position -794, with the 5-repeat allele displaying lower promoter activity. We aimed at assessing the association of this polymorphism with disease severity in a group of Cystic Fibrosis patients homozygous for F508del CFTR gene mutation. Genotype frequencies were determined in 189 Cystic Fibrosis and 134 control subjects; key clinical features of patients were recorded and compared among homozygous 5-allele patients and the other MIF genotypes. Patients homozygous for the 5-repeat allele of MIF promoter displayed a slower rate of lung function decline (p = 0.027) at multivariate survival analysis. Multiple regression analysis on age-normalized respiratory volume showed no association of the homozygous 5-repeat genotype with lung function under stable conditions and no correlation with P.aeruginosa chronic colonization. Therefore, only the Homozygous 5-repeat genotype at MIF -794 is associated with milder disease in F508del Cystic Fibrosis patients.

Figure 1. Lung function decline in 185 Cystic Fibrosis patients grouped according to MIF -794 CATT genotypes.

Kaplan-Meier plots relative to age at first acute episode with FEV1 <60% of predicted value. (A) Comparison between patients with MIF 5-5 (homozygous 5-CATT repeats) vs. not 5-5 genotype; (B) comparison between patients with at least one 5-CATT allele vs. the others. Ticks indicate censored subjects follow-up times. “Number at risk” at the bottom indicates the number of patients without acute episodes at a given time interval and whose follow- up extends at least that far into the curve.