Impact of MIF gene promoter polymorphism on F508del cystic fibrosis patients.

Paola Melotti,Patrick Lebecque,Teresinha Leal,Baroukh Maurice Assael,Claudio Sorio,Andrea Mafficini,Emily Pintani,Myriam Ortombina,Xavier Pepermans,Matthaios Speletas

doi:10.1371/journal.pone.0114274

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.

Highlights

Cystic fibrosis (CF) is the most common, severe, inherited disorder in the Caucasian population
Given the involvement of Migration Inhibitory Factor (MIF) in acute inflammation, we focused on FEV1 as primary outcome variable, comparing patients with the 5-5 MIF-CATT genotype to the rest of the cohort
8% of 189 CF patients homozygous for the F508del CFTR mutation carried the 5-5 allele combination for a functional CATT repeat polymorphism in the MIF gene promoter (MIF-CATT), which is expected to be associated with decreased pro-inflammatory activity

Summary

Introduction

Cystic fibrosis (CF) is the most common, severe, inherited disorder in the Caucasian population It is caused by mutations in the CF Transmembrane conductance Regulator (CFTR) gene and mainly characterized by bronchopulmonary disease, pancreatic insufficiency and male infertility. In an in vitro model, the 5-CATT repeat showed significantly lower transcriptional activity when compared to the 6-, 7- or 8-CATT repeat alleles This polymorphism is reported as a TTCA insertion or deletion relative to the 6-repeats genotype in NCBI dbSNP entries rs3063368 and rs36224313 respectively, at the genomic coordinates (UCSC genome browser – hg19) chr22:24235773-24235772. Five percent of healthy subjects are homozygous for the 5-CATT repeat allele Homozygosity for this allele was significantly associated with milder forms of rheumatoid arthritis, suggesting it may have a protective effect. This study aimed at clarifying and validating the association between MIF-CATT repeats and disease severity in a more homogeneous cohort of CF patients with homozygous F508del CFTR mutation. We verified the possible relationship between MIF and age-normalized FEV1 and chronic P. aeruginosa colonization under stable conditions

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