Rationale Acute lung injury (ALI) is a complex inflammatory syndrome with presumed genetic predisposition. Macrophage migration inhibitory factor (MIF) potentially plays a major role in ALI pathogenesis and constitutes a candidate gene for ALI susceptibility. As the short tandem repeat (STR) 5-repeat allele at −794 of the MIF gene reported decreases MIF promoter activity, we examined this STR and the complete SNP variation of the MIF gene in association with susceptibility to ALI in a Spanish population.
Methods DNA samples from 96 healthy controls and 80 severe septic patients were used to genotype the MIF STR and to sequence the entire gene and the ≈2 kb flanking regions. Polyphred 6.0 software was used to detect SNPs, and variation was examined for linkage disequilibrium (LD) using Haploview 3.32. Odds ratio (OR) and 95% confidence interval (CI) for association of individual polymorphisms were assessed with SNPstats. Haplotype associations were evaluated by a sliding-window approach.
Results The 5-allele homozygous genotype at −794 STR was associated with an OR = 11.9 (95% CI 1.4-98.9, p = .01) after inclusion of covariates in the multiple logistic regression model. Sequencing revealed a total of 45 polymorphic loci (13 novel) that were also analyzed for association. None of them were significantly associated with ALI, either individually or in haplotypes. This result is congruent with the fact that neither SNPs nor haplotypes are in strong LD with the STR.
Conclusions Our data suggest that the MIF gene is associated with susceptibility to ALI and support the causality of the STR locus. Genotyping of this STR is required for future association studies as the MIF SNPs examined were not in strong LD with the STR variation.
Funded by Specialized Centers of Clinically Oriented Research P50 HL-073994.