Genetic Polymorphisms of IL6-174G/C, TNF-308G/A, and TNF-238G/A and Risk of Pleural Tuberculosis in Venezuelan Patients

Cytokine gene polymorphisms in Colombian patients with different clinical presentations of tuberculosis

Antananarivo, the capital city of Madagascar, has an endemic focus of tuberculosis (TB). We specifically studied patients with extrapulmonary TB (EPTB) and grouped patients according to infected body site. The strains were characterized by IS6110 fingerprinting and compared with those isolated from patients with pulmonary TB (PTB) during the same period in order to determine the possible association between the genotype and the clinical expression of TB. A total of 316 TB patients were included in this study: 151 individuals with EPTB, 10 with both PTB and EPTB, and 155 with PTB alone. Pleural TB was the major EPTB localization (77%) and was found more often in older patients, while PTB or EPTB in which the localization was other than pleural (other EPTB) was found in younger patients. The male-to-female ratio was slightly higher in pleural TB patients (3.06:1) than in patients with other EPTB (1.35:1). There was no significant difference in the BCG status among patients with PTB, pleural TB, and other EPTB. Analysis of IS6110 patterns showed that 167 patients (52.8%) were assigned to 37 clusters of 2 to 34 patients. Analysis of the IS6110 clusters and the IS6110 families did not show any association with a particular clinical expression of the disease. Patients with PTB or other EPTB were more likely to have strains with one IS6110 copy than patients with pleural TB. The clustering rate was found to be significantly higher in female patients (62%) than in male patients (48%) (P = 0.029), suggesting that Malagasy women were more likely to progress to disease after infection than men.

Single nucleotide polymorphisms (SNP) in genes encoding cytokines influence tuberculosis (TB) outcomes. To characterise genotypes of the SNPs IFN-gamma +874 T > A, TNF-alpha -308 G > A, IL-6 -174 G > C, IL-10 -1082A > G, TGF-beta codon 10 T > C, and TGF-beta codon 25 G > C in patients with pulmonary (PTB) and extrapulmonary TB (EPTB). 82 PTB and 45 EPTB cases were compared, concerning genotype distribution of the mentioned SNPs, characterised via sequence-specific primer polymerase chain reaction (PCR). Regarding IFN-gamma +874 T > A, AA genotype was the most frequent in both groups, TA was more frequent in PTB and TT in EPTB, with no statistical significance. For SNP TNF-alpha -308 G > A, GG was more frequent in both groups of patients. Regarding the IL-6 -174 G > C polymorphism, GG predominated in both groups, while CG and GG were significantly more frequent in patients with PTB and EPTB, respectively. Concerning IL-10 -1082 A > G, AA predominated in both PTB and EPTB. Concerning TGF-beta codon 10 T > C, CC predominated in PTB while TC predominated in EPTB, but the differences were not statistically significant. Genotype GG of TGF-beta codon 25 G > C predominated among PTB and EPTB patients. Except for IL-6, the genotype profile could not differentiate PTB and EPTB. Hence, the studied SNPs are not significantly associated with the extrapulmonary involvement of TB.

Epidemiology News

Pleural Tuberculosis in the United States: Incidence and Drug Resistance

Background:Pediatric tuberculosis (TB) is an indicator of the recent transmission of TB in the community. However, the diagnosis of pediatric TB poses a challenge to clinicians.Aims:We aimed to evaluate and compare the clinical and laboratory profile of pulmonary TB (PTB) and extra PTB (EPTB) in children and adolescents.Methods:In this retrospective observational study, children attending the pediatric TB clinic of All India Institute of Medical Sciences, Rishikesh, from August 2015 to July 2017 were included in the study. The medical case records of patients were reviewed for demography, clinical findings, investigations, and diagnosis. The clinical and laboratory characteristics of patients with PTB and EPTB were compared.Results:A total of 58 children included. Out of which, 33 (56.9%) had PTB, and 25 (43.1%) had EPTB. The EPTB cases included 15 (60%) pleural TB, 9 (36%) lymph node TB, and 1 (4%) TB meningitis patient. Fever, cough, and weight loss were the most common symptoms. Hilar lymphadenopathy was the most common radiological abnormality. Microbiological confirmation was possible in 54.5% of patients with PTB. Cough (aOR 70.326; 95% CI: 5.370–921.032) and microbiological confirmation (aOR 46.011; 95% CI: 2.073–1021.201) were more in PTB as compared to EPTB.Conclusions:PTB and EPTB are common in children and adolescents. The typical clinical manifestations and positive microbiological confirmation are less common in EPTB than PTB.Relevance for patients:TB is one of the common communicable diseases in the developing world. Diagnosis of TB in children is often challenging. Our study results help in better understanding childhood TB and EPTB clinical features and have potential to increase diagnostic yield.

The autophagy pathway is a critical process in Mycobacterium tuberculosis infection, and can be regulated by uncoordinated 51-like kinase 1 (ULK1). We investigated the associations between single-nucleotide polymorphisms (SNPs) in ULK1 and risk of tuberculosis (TB) in a Chinese Han population. We recruited 380 pulmonary tuberculosis (PTB) cases, 242 extra-pulmonary tuberculosis (EPTB) cases and 606 healthy controls from a Chinese Han population and sequenced ULK1. Five SNPs in ULK1 were selected to investigate the correlations between ULK1 polymorphisms and TB susceptibility. The rs7138581 C allele was associated with a reduced risk of PTB (P = 0.001), whereas the rs9481 A allele was associated with an increased risk (P = 0.025). The rs7138581 CG genotype was significantly associated with a low risk of PTB, with a higher PTB disease severity in clinical parameters. Estimation of haplotype frequencies in ULK1 revealed a protective haplotype CCGAA (P = 0.007) and a potential risk haplotype TGAAA (P = 0.010) for PTB. These results demonstrated that ULK1 polymorphisms have significant associations with susceptibility to PTB.

Current Concepts in the Management of Tuberculosis

A case-control study was conducted to investigate the SNPs at CD59 rs1047581, rs7046, rs2231460, rs184251026, rs41275164, rs831633, rs704700, rs41275166, and rs10768024 by sequence-specific primer-polymerase chain reaction (SSP-PCR) in 900 tuberculosis patients and 1,534 controls. The minor allele frequencies at rs2231460, rs184251026, rs41275164, and rs41275166 were extremely low both in the Cases (0.00%-0.61%) and in the Controls (0.07%-0.43%), comparatively at rs1047581, rs7046, rs831633, rs704700, and rs10768024 were notably higher both in the Cases (8.23%-48.39%) and in the Controls (8.57%-47.16%). Among the nine SNPs, only homozygous CC genotype at rs10768024 showed a significant protective effect against TB than homozygous TT genotype (OR(95% CI) = 0.59(0.38, 0.91), χ 2 = 5.779, P = 0.016), and homozygous TT and heterozygous CT genotypes showed a significant risk of TB infection in the recessive model (OR(95% CI) = 1.68(1.10, 2.56), χ 2 = 5.769, P = 0.016). Further analysis verified that rs10768024 CC genotype independently related to TB susceptibility (OR(95% CI) = 0.60(0.39, 0.91), Wald χ 2 = 5.664, P = 0.017) in multivariate logistic regression analysis, and its genetic mutation was independent of the other SNPs (r 2 = 0.00-0.20) in haplotype analysis. The first investigation of the CD59 gene and susceptibility to TB suggests a significant risk with homozygous TT and heterozygous CT genotypes at rs10768024 loci. The homozygous CC mutation at rs10768024 loci showed a significant protection against TB susceptibility.

This study aimed at highlighting some demographic and clinical features of tuberculosis (TB) at Leon Bernard TB unit, Algeria. This was a retrospective and descriptive study based on TB data extracted from TB patient records during 2009-2019 at Leon Bernard TB unit. Of the total 1375 TB patients, 602 (43.8%) had extrapulmonary TB (EPTB), 482 (35.1%) had new sputum smear-positive pulmonary TB (PTB), 42 (3.1%) had sputum smear-negative with culture-positive PTB, and 97 (7%) EPTB patients had concomitant pulmonary involvement. The male-to-female ratio was 1.07. A total of 116 (8.4%) TB relapses were reported with predominance among ETPB cases (54.3%). Lymphadenitis TB was the most common manifestation of EPTB with 301 cases (39.6%), followed by pleural TB with 237 cases (31.2%). The number of bacteriologically not confirmed EPTB was 22.6% more than half (53.3%) of whom were pleural TB. Among patients with new sputum smear-positive PTB, 71.2% were males, whereas the reverse was observed among patients with EPTB where 62.3% were female. Two-third of recorded cases were between 15 and 45 years old. Nearly all children had EPTB (64/69). The results revealed that most of the patients who passed away were affected by PTB (15/18), and the most frequent cmorbidities were diabetes (9/18) and high blood pressure (6/18). Specific attention needs to be given to an examination of the risk factors of PTB among male population and of EPTB among female population and children and to diagnosis of pleural TB and primary PTB.

BackgroundMycobacterium tuberculosis infection is a leading cause of infectious death worldwide. Gene-expression microarray studies profiling the blood transcriptional response of tuberculosis (TB) patients have been undertaken in order to better understand the host immune response as well as to identify potential biomarkers of disease. To date most of these studies have focused on pulmonary TB patients with gene-expression profiles of extra-pulmonary TB patients yet to be compared to those of patients with pulmonary TB or sarcoidosis.MethodsA novel cohort of patients with extra-pulmonary TB and sarcoidosis was recruited and the transcriptional response of these patients compared to those with pulmonary TB using a variety of transcriptomic approaches including testing a previously defined 380 gene meta-signature of active TB.ResultsThe 380 meta-signature broadly differentiated active TB from healthy controls in this new dataset consisting of pulmonary and extra-pulmonary TB. The top 15 genes from this meta-signature had a lower sensitivity for differentiating extra-pulmonary TB from healthy controls as compared to pulmonary TB. We found the blood transcriptional responses in pulmonary and extra-pulmonary TB to be heterogeneous and to reflect the extent of symptoms of disease.ConclusionsThe transcriptional signature in extra-pulmonary TB demonstrated heterogeneity of gene expression reflective of symptom status, while the signature of pulmonary TB was distinct, based on a higher proportion of symptomatic individuals. These findings are of importance for the rational design and implementation of mRNA based TB diagnostics.

Objective To investigate the relationship between single nucleotide polymorphism (SNP) of type I interferon receptor 1 (IFNAR1) and susceptibility to tuberculosis in the Han population in southern China. Methods A case-control study was used, with 1 533 patients with active tuberculosis (including 1 432 tuberculosis and 101 extrapulmonary tuberculosis) as the case group, and 1 445 healthy people as the control group. Interferon (IFN) gene rs72552343, rs2834191, rs1012334, rs17875752, rs2843710, rs1041868 genotypes were detected by MassARRAY time-of flight mass spectrometry. The differences in the frequency of SNP alleles between the two groups were analyzed, and the differences in the frequency of rs72552343 TCC / Del locus in patients with pulmonary tuberculosis and extrapulgative tuberculosis were further compared. Results MassARRAY time-of-flight mass spectrometry can effectively detect the genotypes of six SNP loci. Among the 6 SNP loci, it was found that only the rs72552343 TCC/Del locus allele frequency was significantly different between the active tuberculosis group and the control group, and the rs72552343 TCC/Del locus TCC allele frequency was significantly increased ( OR =0.46; 95% CI =0.31 -0.70; P =0.000 2), the frequency of the other five SNP alleles was not significantly different between the two groups. In addition, the frequency of TCC alleles at rs72552343 TCC / Del loci in patients with extrapulmonary tuberculosis was not significantly different from that in patients with tuberculosis ( OR =0.88; 95% CI =0.20-3.74; P =0.86). Conclusion The IFN gene rs72552343 TCC / Del site SNP is related to susceptibility to tuberculosis. The TCC allele is a susceptibility gene for tuberculosis, but individuals carrying the TCC allele have the same risk of active pulmonary tuberculosis as those with extrapulmonary tuberculosis. 摘要：目的 探究Ⅰ型干扰素受体 1 (typeⅠinterferon receptor 1, IFNAR1) 单核苷酸多态性 (single nucleotide poly⁃ morphism, SNP) 与结核病易感性的关系。 方法 应用病例-对照研究方法, 以深圳市第三人民医院 1 533 例活动性结核 病患者 (包括 1 432 例肺结核、101 例肺外结核) 作为病例组, 1 445 例健康人群作为对照组。运用 MassARRAY 飞行时间 质 谱 技 术 , 通 过 检 测 Ⅰ 型 干 扰 素 (interferon, IFN) 基 因 rs72552343、rs2834191、rs1012334、rs17875752、rs2843710、rs1041868 位点基因型, 分析两组间 SNP 等位基因频率差异, 同时进一步比较肺结核与肺外结核病患者 rs72552343 TCC/Del 位点等位基因频率差异。 结果 用 MassARRAY 飞行时间质谱技术可以有效地检测 6 个 SNP 位点基因型。在 6 个 SNP 位点中, 发现仅 rs72552343 TCC/Del 位点等位基因频率在活动性结核组和对照组中差异有统计学意义 ( P 0.05)。另外, 发现肺外结核病患者 rs72552343 TCC/Del 位点 TCC 等位基因的频率与肺结核病患者差异无统计学意 义 ( OR =0.88; 95% CI =0.20~3.74; P =0.86)。 结论 IFN 基因 rs72552343 TCC/Del 位点 SNP 与结核易感性相关, 其 TCC 等位基因为结核易感基因, 但携带 TCC 等位基因的个体患活 动性肺结核与肺外结核的风险一致。

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response (VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene–gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test P value = 1.5 × 10−5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

Limited information exists about the current epidemiological characteristics of extrapulmonary tuberculosis. However, pleural tuberculosis is usually considered to be a manifestation of primary tuberculosis. Our objective was to use molecular epidemiological techniques to describe the occurrence of pleural and other extrapulmonary tuberculosis in Maryland, a state with moderate tuberculosis incidence. We surveyed tuberculosis cases reported with a single site of disease in Maryland from 1996 through 2001. Genotyping of Mycobacterium tuberculosis isolates was performed with an IS6110-based restriction fragment-length polymorphism analysis. DNA clustering of strains with >5 IS6110 bands, with supporting epidemiologic information on patients, served as a proxy for recent transmission. A total of 1811 patients with tuberculosis were reported (incidence, 5.9 cases per 100,000 population). Of 1411 patients (77.9%) with cultures positive for M. tuberculosis, 1246 (88.3%) had a single site of disease, with 934 (75.0%) of these isolates having >5 IS6110 bands. Of the 934 patients included in the analyses, 729 (78.0%) had pulmonary tuberculosis, and 205 (22.0%) had extrapulmonary tuberculosis; of the latter group, 46 patients had pleural disease, and 159 patients had nonrespiratory disease. In multivariate analyses, patients with pleural tuberculosis were not significantly associated with clustered strains, compared with patients with nonrespiratory or pulmonary tuberculosis disease. Having a DNA-clustered strain was negatively associated with nonrespiratory tuberculosis, compared with pulmonary disease (adjusted odds ratio, 0.48; P = .003). Nonrespiratory extrapulmonary tuberculosis is less likely than pulmonary tuberculosis to be a result of recent infection. Pleural tuberculosis is not an appropriate indicator for recent transmission among our population.

Background: Single nucleotide polymorphisms (SNPs) within precursor microRNAs (miRNAs) can affect the expression of the miRNAs and may be involved in the pathogenesis of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB). Aims: We investigated the potential associations among four precursor miRNA SNPs (miR-149 A>G, C>T; miR-196a2 C>T; miR-499 C>T) and both PTB and EPTB. Methods: The study included 380 PTB patients, 242 EPTB patients, and 606 healthy control (HC) subjects from a Chinese Han population. We determined the miRNA relative expression levels from 10 HCs and 10 tuberculosis (TB) patients by quantitative PCR. Results: We found that the PTB group had a significantly lower miR-149 level (p < 0.05) versus the HCs. The allele and genotype frequencies of the miR-149 SNPs were significantly different between the TB patients and the HC group. The C allele at the rs2292832 and the A allele at the rs71428439 locus were associated with susceptibility to EPTB. The C allele of rs2292832 was associated with an increased risk of EPTB compared with that of HCs (p < 0.01), and the A allele of rs71428439 was protective against EPTB (p < 0.01) and PTB (p < 0.01). Conclusions: We identified genetic polymorphisms in miR-149 that appear to be associated with susceptibility to both PTB and EPTB within a Chinese population.