The Relationship between Functional Promoter Variants of Macrophage Migration Inhibitory Factor and Endometriosis

Objective: Endometriosis is a common gynecological and inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory cytokine that is secreted by accumulated active macrophages in ectopic endometrial tissues. Two promoter polymorphisms of MIF [-794(CATT)(5-8)/-173G/C] were identified to susceptibility and severity of several immune and inflammatory diseases. We aimed to evaluate the possible association between MIF promoter polymorphisms and susceptibly to endometriosis and its corolation with mRNA level. Materials and Methods: This case-control study was performed in Royan Institute from 2015 to 2017. Polymorphisms were evaluated in 106 endometriosis patients and 110 controls. For 17 endometrioma tissues, gene expression studies were conducted during secretory phase of menstrual cycle. Restriction fragment length polymorphism (RFLP) analysis was performed to determine -173G/C polymorphism and -794(CATT)(5-8) were detected by sequencing. Quantitative polymerase chain reaction (Q-PCR) was carried out to determine MIF expression level. Results: Homozygote of CATT(7) was observed only in endometriosis whilst we did not detect the significant allele and genotype variation in both groups. The homozygotes for -794(CATT)(5-8) and -173G/C polymorphisms were obtained to estimate the haplotype frequencies. Significantly higher haplotype frequencies were observed for CATT(5)/G in controls [global P value=0.044]. Additionally, the CATT(5)/C and CATT(7)/G haplotypes were not detected in any groups. Expression level of mRNA in ectopic tissue of endometriosis patients with CATT(6,7)/CC haplotype, were significantly higher compared to other haplotypes including CATT(5,5)/GG (2.91 fold, P=0.007), CATT(5,5)/GC (2.48 fold, P=0.047) and CATT(6,6)/GG (2.08 fold, P=0.046). Conclusion: We report, for the first time, a strong linkage between the decreased repetition of CATT and G allele in control and CATT(6)/C and CATT(7)/C haplotypes in endometriosis patients. Increased MIF expression is affected by genetic variants in the MIF promoter in ectopic endometrial tissues. This promoter haplotype might play an important role in the development and establishment of endometriosis.