A polymorphism in human CD1A is associated with susceptibility to tuberculosis.
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ABSTRACT:
SUBMITTER: Seshadri C
PROVIDER: S-EPMC3998877 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The MR1 antigen-presenting system is conserved among mammals and enables T cells to recognize small molecules produced by bacterial pathogens, including Mycobacterium tuberculosis (M.tb). However, it is not known whether MR1-mediated antigen presentation is important for protective immunity against mycobacterial disease. We hypothesized that genetic control of MR1 expression correlates with clinical outcomes of tuberculosis infection. We performed an MR1 candidate gene association study and identified an intronic single-nucleotide polymorphism (rs1052632) that was significantly associated with susceptibility to tuberculosis in a discovery and validation cohort of Vietnamese adults with tuberculosis. Stratification by site of disease revealed that rs1052632 genotype GG was strongly associated with the development of meningeal tuberculosis (odds ratio=2.99; 95% confidence interval (CI) 1.64-5.43; P=0.00006). Among patients with meningeal disease, absence of the G allele was associated with an increased risk of death (hazard ratio=3.86; 95% CI 1.49-9.98; P=0.005). Variant annotation tools using public databases indicate that rs1052632 is strongly associated with MR1 gene expression in lymphoblastoid cells (P=0.004) and is located within a transcriptional enhancer in epithelial keratinocytes. These data support a role for MR1 in the pathogenesis of human tuberculosis by revealing that rs1052632 is associated with MR1 gene expression and susceptibility to tuberculosis in Vietnam.
| S-EPMC5269436 | biostudies-literature
Project description:Objective:To date, a series of studies were conducted to investigate the association between TLR2 (Toll-like receptor 2) Arg753Gln gene polymorphism and tuberculosis (TB). However, the results were inconsistent. This meta-analysis was performed to elucidate the roles of TLR2 Arg753Gln gene polymorphism in TB. Methods:All available articles were searched from online databases such as PubMed, Medline, CNKI, and Wanfang. Statistical analyses were performed using the STATA12.0 (Stata Corp LP, College Station, TX, United States) software. Results:32 case-control studies comprising 5943 cases and 5991 controls were identified in this meta-analysis. Overall, the TLR2 Arg753Gln gene polymorphism was associated with high TB risk in allele model (A vs. G: OR=2.20, 95%CI=1.60-3.04, P?0.01), dominant model (AA+AG vs. GG: OR=2.70, 95%CI=2.00-3.65, P?0.01), and heterozygote model (AG vs. GG contrast: OR=2.97, 95%CI=2.39-3.69, P?0.01). Subgroup analysis by ethnicity indicated that the A allele increased susceptibility to TB in Asian (OR=3.35, 95%CI=2.36-4.74) and Caucasian populations (OR=2.62, 95%CI=1.77-3.87), but not in African (2.08, 95%CI=0.62-2.72) or mixed populations (OR=0.76, 95%CI=0.36-1.14). Stratified analysis by sample type suggested that the A allele associated with high pulmonary tuberculosis (PTB) risks (OR=2.43, 95%CI=1.66-3.54), but not with extra pulmonary tuberculosis (EPTB) (OR=1.84, 95%CI=0.83-4.06). Conclusion:this meta-analysis suggested the following: (1) TLR2 Arg753Gln polymorphism is significantly associated with high TB risk. (2) In subgroup analysis based on ethnicity, TLR2 Arg753Gln polymorphism elevates the risk of TB in Asian and Caucasian populations, but not in African or mixed populations. (3) Stratified by sample type, TLR2 Arg753Gln polymorphism is associated with increased PTB risk, but not with EPTB.
| S-EPMC6348792 | biostudies-literature
Project description:BackgroundNuclear transcription factor erythroid 2 p45-related factor 2 (Nrf2), encoded by NFE2L2, functions as a key transcription factor and regulates expression of antioxidant genes. Our study aimed to investigate the association of single nucleotide polymorphisms of NFE2L2 with tuberculosis (TB) and latent tuberculosis infection (LTBI) and the underlying causal mechanisms.Methods1950 unrelated Chinese Han participants were included in our two independent study groups. Five tag polymorphisms were selected and genotyped. The functional effects of the rs13005431 polymorphism were confirmed by dual-luciferase reporter assays and mRNA level comparisons.ResultsRs13005431_C and rs2364723_G were associated with increased TB susceptibility (P = 0.010 and P = 0.041) after adjustment for confounding factors. rs6726395_A was associated with increased risk of active TB (P=0.035) in a comparison with the LTBI group. The frequency of haplotype rs1049751- rs13005431 AC was higher in the TB group (P =0.013), while frequency of haplotype AT was higher in the healthy control group (P =0.025). The luciferase activity of a plasmid with the rs13005431C-promoter was significantly lower than that of the rs13005431T-promoter. In addition, neutrophils with the CC/TC genotypes which were activated by GM-CSF showed a decreased level of NFE2L2 mRNA when compared with the rs13005431 TT genotype.ConclusionsOur study suggests that allele C of rs13005431 might increase the susceptibility to TB by down-regulating the transcriptional activity of NFE2L2.
| S-EPMC8181729 | biostudies-literature
Project description:BACKGROUND: The melanocortin-3-receptor (MC3R) is a member of the G-protein coupled receptor family that mediate cellular response through the cyclic adenosine monophosphate signalling pathway. In the promoter region of MC3R the polymorphism rs6127698 has previously been shown to be strongly associated with tuberculosis susceptibility. It is predicted to generate an alternative transcription factor binding site. FINDINGS: We investigated the functional impact of rs6127698 by luciferase assay to assess if this polymorphism is capable of altering protein expression. Our results did not show any significant protein expression changes when comparing the two alleles of rs6127698. CONCLUSIONS: Our experiments demonstrate that the rs6127698 polymorphism does not influence protein translation. A functional role of the predicted alternative transcription factor binding site could therefore not be confirmed. These results suggest rs6127698 has no direct role in tuberculosis susceptibility. The possibility remains that this polymorphism is linked to an adjacent functional genetic variant, acting as a surrogate marker for disease risk.
| S-EPMC3605127 | biostudies-literature
Project description:ObjectiveThe T allele of C-reactive protein (CRP) +1444C/T (rs1130864) polymorphism was associated with increased risk for some inflammatory conditions. The objective of the study was to explore the association between the CRP +1444C/T polymorphism with the susceptibility to pulmonary tuberculosis (PTB) in a Chinese population.MethodsThis case-control study enrolled 480 PTB patients and 480 healthy controls. The CRP +1444C/T polymorphism was determined using Sanger sequencing. The odds ratio (OR) and 95% confidence interval (CI) were assessed to examine the strength of genetic correlation.ResultsThe genotype and allele frequencies of PTB patients differed from controls (CT vs. CC, OR = 1.924, 95% CI: 1.099-3.371, adjusted?P?value = 0.022; T vs. C, OR = 1.884, 95% CI: 1.085-3.273, adjusted?P?value = 0.024). Stratified analysis by sex found that PTB patients' genotype and allele frequencies differed from controls in the male subgroup but not the female subgroup.ConclusionIn conclusion, the minor T allele of CRP +1444C/T polymorphism was associated with increased PTB risk.
| S-EPMC7769630 | biostudies-literature
Project description:Tuberculosis (TB) is still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leukocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian populations. Case-control studies have found the association of HLA-DR2 in some populations, but not in other populations, this could be due to an ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB.
| S-EPMC6106802 | biostudies-literature
Project description:Introduction. Tuberculosis (TB) is a major disease worldwide, caused by Mycobacterium tuberculosis (MTB) infection. The Toll-Like Receptor (TLR) pathway plays a crucial role in the recognition of MTB. Aim. The present study aimed to investigate the involvement of myeloid differentiation primary response protein 88 (MYD88) gene polymorphisms in TB. Materials and Methods. A total of 103 TB cases and 92 control subjects were genotyped for the MYD88 -938C>A (rs4988453) and 1944C>G (rs4988457) polymorphisms. Results. The MYD88 -938CA and -938AA genotypes were associated with an increased risk for tuberculosis with odds ratio (OR) of 5.71 (95% confidence intervals [CIs] 2.89-11.28, p = 0.01). Conclusions. The MYD88 -938C>A genetic polymorphism is associated with increased susceptibility to TB and may serve as a marker to screen individuals who are at risk.
| S-EPMC5227150 | biostudies-literature
Project description: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.
| S-EPMC6329172 | biostudies-literature
Project description:A susceptibility locus for tuberculosis, a re-emerging infectious disease throughout the world, was previously discovered to exist on chromosome 11p15. IFITM3 gene encoding for interferon inducible transmembrane protein 3, is located at 11p15. It acts as an effector molecule for interferon-gamma, which is essential for anti-tuberculosis immune response. In order to investigate the association between susceptibility to TB and genetic polymorphisms of the IFITM3 core promoter, a case-control study including 368 TB patients and 794 healthy controls was performed in Han Chinese children in northern China. The rs3888188 polymorphism showed significant association with susceptibility to TB. The rs3888188 G allele, acting recessively, was more frequent in TB patients (95% confidence interval: 1.08-1.56, Bonferroni P-value: 0.039). We further assessed the effect of rs3888188 polymorphism on IFITM3 transcription in vitro. As based on luciferase promoter assays, the promoter activity of haplotypes with rs3888188 G allele was lower than that of haplotypes with rs3888188 T allele. Moreover, peripheral-blood mononuclear cells carrying rs3888188 GG genotype showed a reduced IFITM3 mRNA level compared to cells carrying TT or GT genotype. In conclusion, rs3888188, a functional promoter polymorphism of IFITM3, was identified to influence the risk for pediatric TB in Han Chinese population.
| S-EPMC3706438 | biostudies-literature
Project description:CD1 proteins evolved to present diverse lipid Ags to T cells. In comparison with MHC proteins, CD1 proteins exhibit minimal allelic diversity as a result of nonsynonymous single nucleotide polymorphisms (SNPs). However, it is unknown if common SNPs in gene regulatory regions affect CD1 expression and function. We report surprising diversity in patterns of inducible CD1a expression on human dendritic cells (DCs), spanning the full range from undetectable to high density, a finding not seen with other CD1 isoforms. CD1a-deficient DCs failed to present mycobacterial lipopeptide to T cells but had no defects in endocytosis, cytokine secretion, or expression of costimulatory molecules after LPS treatment. We identified an SNP in the 5' untranslated region (rs366316) that was common and strongly associated with low CD1a surface expression and mRNA levels (p = 0.03 and p = 0.001, respectively). Using a CD1a promoter-luciferase system in combination with mutagenesis studies, we found that the polymorphic allele reduced luciferase expression by 44% compared with the wild-type variant (p < 0.001). Genetic regulation of lipid Ag presentation by varying expression on human DCs provides a mechanism for achieving population level differences in immune responses despite limited structural variation in CD1a proteins.
| S-EPMC3748949 | biostudies-literature