ABSTRACT
BACKGROUND: Host genetic factors affect the immune response to Mycobacterium tuberculosis (Mtb) infection as well as the progression of the disease. Epiregulin (EREG) belongs to the epidermal growth factor (EGF) family, which binds to the epidermal growth factor receptor (EGFR) to regulate the immune response of the host during infections. Our study aimed to compare EREG levels in tuberculosis (TB) patients and healthy controls and assess whether polymorphisms in EREG increase the risk of TB. METHODS: We used ELISA to determine the plasma EREG level from 30 healthy controls and 50 tuberculosis patients. By evaluating the EREG gene from 624 TB patients and 600 healthy controls, we determined the allelic and genotypic frequencies for association with susceptibility to TB infections in this group. RESULTS: This paper shows that the pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) groups showed a significantly higher plasma EREG level (1014 ± 733.9 pg/ml, 700.2 ± 676.6 pg/ml, respectively) than the healthy controls (277 ± 105.4 pg/ml). The rs2367707 polymorphism was associated with a higher risk of PTB and EPTB (P = 0.00051, P = 0.0012). Analyses of haplotype frequencies found that people with the haplotype CACAT had a higher risk of PTB and EPTB (P = 0.00031, OR = 1.43; P = 0.000053, OR = 1.65). Moreover, the rs6446993 polymorphism of the EREG gene was found to be associated with EPTB (P = 0.00087, OR = 1.54; 95% CI = 1.23-1.94). CONCLUSIONS: Compared to that of healthy controls, the level of EREG in the plasma of TB patients increased significantly. Based on these data, we demonstrated that EREG polymorphisms are genetic factors for susceptibility to TB and various forms of TB.
Subject(s)
Epiregulin/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Tuberculosis/genetics , Adolescent , Adult , Alleles , Case-Control Studies , Child , China , Disease Progression , Epiregulin/blood , Epiregulin/immunology , Female , Genotype , Haplotypes , Humans , Linkage Disequilibrium , Male , Middle Aged , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/genetics , Young AdultABSTRACT
BACKGROUND: Hepcidin is a 25-amino acid peptide produced by the liver in response to inflammation and iron overload. It is encoded by the hepcidin antimicrobial peptide (HAMP) gene and plays a key role in innate immunity. Previous studies have reported that a -582 A>G polymorphism in the HAMP promoter (HAMP-P) affects hepcidin expression, causing susceptibility to various bacterial and viral pathogens. However, it is not known whether the HAMP-P -582 A>G polymorphism is associated with tuberculosis (TB) susceptibility. AIMS: The objective of the current study was to examine the relationship between the HAMP-P -582 A>G polymorphism and TB susceptibility in a Chinese Han population. METHODS: Han Chinese subjects examined included 500 pulmonary TB, 386 extrapulmonary TB, and 600 healthy control subjects. We analyzed correlations between the hepcidin promoter -582 A>G polymorphism and disease susceptibility and then examined the regulatory effects of the -582 A>G variant on hepcidin production in CD14+ monocyte cultures stimulated with lipoarabinomannan derived from Mycobacterium tuberculosis. RESULTS: Our findings indicate that the HAMP-P -582 A>G polymorphism (rs10421768) is associated with susceptibility to extrapulmonary TB, but not pulmonary TB. CD14+ monocytes from individuals with the rs10421768 GG genotype secreted significantly less hepcidin in response to M. tuberculosis lipoarabinomannan compared with cells from individuals with either the AA or AG genotypes. CONCLUSIONS: The G allele of the HAMP-P -582 A>G gene may play a critical role in TB susceptibility.
Subject(s)
Hepcidins/genetics , Tuberculosis, Pulmonary/genetics , Adult , Case-Control Studies , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease/genetics , Hepcidins/metabolism , Humans , Male , Middle Aged , Nucleotides , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/genetics , Tuberculosis/geneticsABSTRACT
OBJECTIVES: Prostaglandin E2 (PGE2) is an important lipid mediator of the inflammatory immune response during acute and chronic infections. PGE2 modulates a variety of immune functions via four receptors (EP1-EP4), which mediate distinct PGE2 effects. Mice lacking EP2 are more susceptible to infection by Mycobacterium tuberculosis (M.tb), have a higher bacterial load, and increase size and number of granulomatous lesions. Our aim was to assess whether single nucleotide polymorphisms (SNPs) in EP2 increase the risk of tuberculosis. METHODS: DNA re-sequencing revealed five common EP2 variants in the Chinese Han population. We sequenced the EP2 gene from 600 patients and 572 healthy controls to measure SNP frequencies in association with tuberculosis infections (TB) within the population. RESULTS: The rs937337 polymorphism is associated with increased risk to tuberculosis (p=0.0044, odds ratio [OR], 1.67; 95% confidential interval,1.22-2.27). The rs937337 AA genotype and the rs1042618 CC genotype were significantly associated with TB. An estimation of the frequencies of haplotypes revealed a single protective haplotype GACGC for tuberculosis (p=0.00096, odds ratio [OR], 0.56; 95% confidential interval, 0.41-0.77). Furthermore, we determined that the remaining SNPs of EP2 were nominally associated with clinical patterns of disease. CONCLUSIONS: We identified genetic polymorphisms in EP2 associated with susceptibility to tuberculosis within a Chinese population. Our data support that EP2 SNPs are genetic predispositions of increased susceptibility to TB and to different clinical patterns of disease.
