A Correlation between Macrophage Migration Inhibitory Factor (MIF) Gene Promoter Polymorphism and Susceptibility to Active Pulmonary Tuberculosis in Yunnan Population, China

Abstract

Tuberculosis (TB) is a infectious disease caused by the bacterium Mycobacterium tuberculosis (Mtb), which resulted in estimated 10.4 million new cases and 1.7 million deaths in 2016 and still is serious health problem in the word. Approximately 1/3 of the world's population carry the disease but don't have any symptoms, however approximately 10% of these people will likely develop active disease during their lifetime and able to transmit the bacterium, but the exact pathogenesis of TB is not clarified yet and is urgent to be studied. The MIF gene encoding macrophage migration inhibitory factor (MIF) has been proposed as candidate tuberculosis (TB) susceptibility gene and need to be deeply explored. The aim of this study was to extensively investigate the potential association between the -173 G/C single-nucleotide polymorphisms and −794 CATT5-8 microsatellite polymorphism of the MIF gene and susceptibility to new cases and retreatment cases of TB, respectively, and to systematically evaluate the correlation between functional G/C SNP and CATT microsatellite polymorphisms in the MIF gene promoter regions and the susceptibility to new cases and retreatment cases of TB, which are one of the dominant drug-resistant TB pools. In order to elucidate whether MIF gene variants are associated with susceptibility to retreatment cases of TB, and prevent drug-resistant TB prevalence, we conducted a study based on paired human population data. Genotypes of MIF -173 G/C single nucleotide polymorphisms (SNP) and MIF -794 CATT5-8 microsatellite polymorphisms among 200 tuberculosis (TB) patients and 100 healthy controls were performed to study the relationships between G/C polymorphism at position -173 and TB or between CATT polymorphism at position -794 and TB in new patients and retreatment cases, respectively. Significant increases in MIF - 173 G/C and -794 CATT, genotype GC + CC (60.0% vs. 43.0%, OR = 0.503, 95% CI = 0.309-0.818, p < 0.01), genotypes 7/8 (6.0% vs. 1.0%, OR = 6.32, 95% CI = 0.81- 49.31, p < 0.05) and allele CATT 8 (3.0% vs. 0.5%, OR = 6.15, 95% CI = 0.79-47.67, p < 0.05), were observed in TB patients compared with the controls. Moreover, significant differences in the genotypic frequencies of MIF -173 G/C (GG vs. GC+CC) were demonstrated upon comparing the total cases, the new cases of TB and the retreatment cases of TB with the controls (OR = 1.99, 95% CI = 1.22-3.24, p < 0.01, OR = 1.83, 95% CI = 1.05-3.21, p < 0.05, and OR = 2.16, 95% CI = 1.23-3.81, p < 0.05, respectively), and MIF -794 CATT (5/X + 6/X vs. 7/7+ 7/8) were also proved upon comparing the total cases and the new cases of TB with the controls (OR = 5.57, 95% CI = 1.32-25.03, p < 0.05, and OR = 7.32, 95% CI = 1.61-33.36, p < 0.01, respectively). Significant differences in the allelic frequencies of MIF -794 CATT (5+ 6 vs. 7+8) were observed in the total cases (OR = 0.53, CI=0.33-0.86, p <0.05) and new cases of TB (OR = 2.09, CI = 1.23-3.56, p < 0.01) compared with the controls. The results suggested that MIF -173 G/C genotype (GC + CC) was associated with the total cases, new cases of TB, and retreatment cases of TB, and MIF -794 CATT genotypes (7/7+7/8) and alleles (7+8) were associated with both the total cases and new cases of TB. However, types of MIF -173 G/C allele were not related to TB susceptibility. Significant increases in the MIF serum concentrations in TB cases with the MIF -173 genotypes GG and (GC + CC), -794 genotypes (5/5 + 5/6 + 6/6) and (7/X + 8/X) were detected, compared with the healthy controls (p < 0.05), respectively. Moreover, the MIF levels in the retreatment cases were higher than in the new cases (p < 0.05). In contrast, there were no difference in the MIF concentrations between the MIF 173 G/C genotype GG and (GC + CC), and −794 CATT genotype (5/5+ 5/6+6/6) and (7/X+8/X) within each TB group (p > 0.05). Our results not only further confirm previous conclusions by other authors from studies, but also give a deeper and more extensive insight into the associations between MIF -173 G/C single nucleotide polymorphisms (SNP) and susceptibility to active TB and between MIF -794 CATT5-8 microsatellite polymorphisms and susceptibility to active TB.