To Tuberculosis Disease Research Articles

Transcriptomic signatures of progression to TB disease among close contacts in Brazil.

Approximately 5% of people infected with Mycobacterium tuberculosis progress to tuberculosis (TB) disease without preventive therapy. There is a need for a prognostic test to identify those at highest risk of incident TB, so that therapy can be targeted. We evaluated host blood transcriptomic signatures for progression to TB disease. Close contacts (≥4 hours exposure per week) of adult patients with culture-confirmed pulmonary TB were enrolled in Brazil. Investigation for incident, microbiologically-confirmed or clinically-diagnosed pulmonary or extra-pulmonary TB disease through 24 months of follow-up was symptom-triggered. Twenty previously validated blood TB transcriptomic signatures were measured at baseline by real-time quantitative PCR. Prognostic performance for incident TB was tested using receiver operating characteristic curve (ROC) analysis at 6, 9, 12, and 24 months of follow-up. Between June 2015 and June 2019, 1,854 close contacts were enrolled; Twenty-five progressed to incident TB, of whom 13 had microbiologically-confirmed disease. Baseline transcriptomic signature scores were measured in 1,789 close contacts. Prognostic performance for all signatures was best within 6 months of diagnosis. Seven signatures (Gliddon4, Suliman4, Roe3, Roe1, Penn-Nicholson6, Francisco2, and Rajan5) met the minimum World Health Organization target product profile (TPP) for a prognostic test through 6 months; three (Gliddon4, Rajan5, and Duffy9) through 9 months. None met the TPP threshold through 12 or more months of follow-up. Blood transcriptomic signatures may be useful for predicting TB risk within 9 months of measurement among TB-exposed contacts, to target preventive therapy administration.

Diagnostic markers reflecting dysregulation of the host response in the transition to tuberculosis disease

Sustained control of Mycobacterium tuberculosis infection without evidence of disease is based on a finely tuned balance between pro- and anti-inflammatory responses. Loss of this balance leads to tuberculosis (TB) disease, in which exacerbated myeloid and neutrophil activation is common. Proteomic and transcriptomic assessment of the host response can detect increasing immune activation associated with TB disease progression several months before clinical disease. Future diagnostic methods based on measuring host response biomarkers that are able to detect this dysregulation could therefore be valuable in the early detection of TB disease progression.

Exploring the ethics of tuberculosis human challenge models

We extend recent conversation about the ethics of human challenge trials to tuberculosis (TB). TB challenge studies could accelerate vaccine development, but ethical concerns regarding risks to trial participants and...

Household costs incurred when seeking and receiving paediatric tuberculosis services: a survey in Cameroon and Kenya

Background Elimination of catastrophic costs due to tuberculosis (TB) is one of the three targets of the World Health Organization (WHO) End TB Strategy. Limited data have yet been reported on the costs experienced by households of children receiving TB services. We quantified the economic impact on households with children seeking and receiving TB services during the Catalyzing Pediatric TB Innovations (CaP-TB) project in Cameroon and Kenya. Methods Within the INPUT stepped-wedge cluster-randomised study evaluating the effect of CaP-TB integration of TB services in paediatric entry points, we designed a cross-sectional facility-based survey with retrospective data collection using a standardised questionnaire adapted from the WHO Global taskforce on TB patient cost generic survey instrument. Caregivers of children receiving TB services (screening, diagnosis and treatment of drug-sensitive TB) during the CaP-TB project were interviewed between November 2020 and June 2021. Direct medical, direct non-medical, and indirect costs for TB services were analysed following WHO Global taskforce recommendations. We used the human capital and output-based approaches to estimating income loss. All costs are presented in 2021 US dollars. Results A total of 56 caregivers representing their households (Cameroon, 26, and Kenya, 30) were interviewed. The median household costs for TB services, estimated using the human capital approach, were $255 (IQR; $130-631) in Cameroon and $120 ($65-236) in Kenya. The main cost drivers across both countries were direct non-medical costs (transportation and food), 52%; and medical costs, 34%. Approximately 50% of households reported experiencing dissavings (taking a loan, or selling an asset) to deal with costs related to TB disease. Using a threshold of 20% of annual household income, 50% (95%CI; 37-63%) of households experienced catastrophic costs when using the human capital approach; (46% (95%CI; 29-65%) in Cameroon and 53% (95%CI; 36-70%) in Kenya). Estimated costs and incidence of catastrophic costs increased when using the output-based approach in a sensitivity analysis. Conclusions Accessing and receiving TB services for children results in high levels of cost to households, despite the provision of free TB services. Strategies to reduce costs for TB services for children need to address social protection measures or explore decentralisation. Registration: https://clinicaltrials.gov/ct2/show/NCT03862261.

Adolescent, caregiver and provider perspectives on tuberculosis treatment adherence: a qualitative study from Lima, Peru

ObjectivesTo understand the perspectives of adolescents (10–19 years old), their caregivers and healthcare providers regarding factors that impact adherence to tuberculosis (TB) treatment among adolescents.DesignWe conducted in-depth interviews using semistructured...

Mycobacterium tuberculosis genetic features associated with pulmonary tuberculosis severity

Mycobacterium tuberculosis (Mtb) infections result in a wide spectrum of clinical presentations but without proven Mtb genetic determinants. Herein, we hypothesized that the genetic features of Mtb clinical isolates, such as specific polymorphisms or microdiversity, may be linked to tuberculosis (TB) severity. A total of 234 patients with pulmonary TB (including 193 drug-susceptible and 14 monoresistant cases diagnosed between 2017 and 2020 and 27 multidrug-resistant cases diagnosed between 2010 and 2020) were stratified according to TB disease severity, and Mtb genetic features were explored using whole genome sequencing, including heterologous single-nucleotide polymorphism (SNP), calling to explore microdiversity. Finally, we performed a structural equation modeling analysis to relate TB severity to Mtb genetic features. The clinical isolates from patients with mild TB carried mutations in genes associated with host-pathogen interaction, whereas those from patients with moderate/severe TB carried mutations associated with regulatory mechanisms. Genome-wide association study identified an SNP in the promoter of the gene coding for the virulence regulator espR, statistically associated with moderate/severe disease. Structural equation modeling and model comparisons indicated that TB severity was associated with the detection of Mtb microdiversity within clinical isolates and to the espR SNP. Taken together, these results provide a new insight to better understand TB pathophysiology and could provide a new prognosis tool for pulmonary TB severity.

Unbalanced serum immunoglobulins in clinical subtypes of pediatric tuberculosis disease.

Immune response to tuberculosis (TB) has been extensively studied in the past decades and classically involves cellular immunity. However, evidence suggests that humoral immunity may play a relevant role. Past studies regarding serum immunoglobulin (Ig) levels in TB are dated and only involve adult subjects. In this study, we retrospectively studied a cohort of 256 children with TB disease and analyzed 111 patients screened for total serum Ig at diagnosis. According to the severity and extent of organ involvement, subjects were divided into four groups, namely, uncomplicated pulmonary TB (UCPTB, 56.3% of patients), complicated pulmonary TB (CPTB, 22.5%), lymph node extrapulmonary TB (LN-EPTB, 7.2%), and extra-nodal extrapulmonary TB (EN-EPTB, 13.5%). Serum IgG and IgA levels were significantly higher in more severe and extended TB disease. Median IgG levels progressively increased from uncomplicated to complicated pulmonary and nodal forms, reaching their highest values in diffuse extra-pulmonary TB. In parallel, UCPTB showed significantly lower frequencies of patients presenting a substantial increase in IgG levels when compared with the other three groups. No relevant differences in IgM levels were detected. Ig screening at follow-up showed a significant reduction in IgG and IgA levels. Finally, we unveiled three cases of selective IgA and one case of selective IgM deficiencies (SIgMD), the latter with a severe clinical course. Serum IgG and IgA may be a useful clinical tool to assess the severity and monitor the treatment response in pediatric TB disease. Moreover, immunological workup in children with TB disease may unmask primary defects of humoral immunity.

Clinical profile and mortality predictors for tuberculosis disease among patients with solid tumours

Background The characteristics of Mycobacterium tuberculosis (MTb) disease are still obscure in patients with solid tumours, as well as the benefits of screening and treating latent tuberculosis infection (LTBI) in these patients. Our objective was to trace the clinical profile of these individuals and assess the mortality predictors related to tuberculosis (TB). Methods We reviewed the medical records of 126 patients with solid tumours malignancy and who developed TB disease between January 2009 and April 2018 at a cancer referral centre. Results The most common locations of malignancy were head and neck, with squamous cell carcinoma being the most frequent histological type, the majority (97/126) presenting locally invasive tumours (T3 or T4). A total of 120 had TB pulmonary and the microbiological diagnosis was performed in 103/126. The following variables were associated with the risk of death from TB: DPOC lung cancer, BMI, malnutrition, metastasis and ECOG 3 or 4. Previous chemotherapy treatment was a protective factor. Conclusions Male, usage of alcohol and smoking were the most predominant patients characteristics in our sample. In the multivariate analysis, lung cancer, presence of metastasis and ECOG ≥ 3 were associated with death from TB.

The paradox of immune checkpoint inhibition re-activating tuberculosis.

By attenuating T-cell activation, immune checkpoints (ICs) limit optimal anti-tumour responses and IC inhibition (ICI) has emerged as a new therapy for a broad range of cancers. T-cell responses are indispensable to tuberculosis (TB) immunity in humans. However, boosting T-cell immunity in cancer patients by blocking the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) axis can trigger re-activation of latent TB. This phenomenon appears to contradict the prevailing thought that enhancing T-cell immunity to Mycobacterium tuberculosis will improve immune control of this pathogen. In support of this anecdotal human data, several murine studies have shown that PD-1 deficiency leads to severe TB disease and rapid death. These observations warrant a serious reconsideration of what constitutes effective TB immunity and how ICs contribute to it. Through restraining T-cell responses, ICs are critical to preventing excessive tissue damage and maintaining a range of effector functions. Bolstering this notion, inhibitory receptors limit pathology in respiratory infections such as influenza, where loss of negative immune regulation resulted in progressive immunopathology. In this review, we analyse the mechanisms of ICs in general and their role in TB in particular. We conclude with a reflection on the emerging paradigm and avenues for future research.

Population-wide active case finding and prevention for tuberculosis and leprosy elimination in Kiribati: the PEARL study protocol

IntroductionPopulation-wide interventions offer a pathway to tuberculosis (TB) and leprosy elimination, but ‘real-world’ implementation in a high-burden setting using a combined approach has not been demonstrated. This implementation study aims...

Prediction Tool to Identify Children at Highest Risk of Tuberculosis Disease Progression Among Those Exposed at Home.

BackgroundThere is a dearth of research to understand which children, among those who are exposed at home to tuberculosis (TB), are at the highest risk of TB disease, to tailor care. We sought to identify predictors of TB progression in children.MethodsWe conducted a prospective cohort study of children living with adults with pulmonary TB in Lima, Peru (2009–2012). We applied classification and regression tree analysis to examine potential predictors of incident TB disease during 12 months in 3 age groups (0–4, 5–9, and 10–14 years). We calculated the relative risk (RR) for top predictors in each age group.ResultsAmong 4545 children 0–14 years old, 156 (3.4%) were diagnosed with TB within 1 year of household exposure to TB (3.4%, 2.3%, and 4.7% in children 0–4, 5–9, and 10–14 years old, respectively). The most important predictor of TB was having a positive tuberculin skin test (TST) result, with RRs of 6.6 (95% CI, 4.0–10.7), 6.6 (95% CI, 3.2–13.6), and 5.2 (95% CI, 3.0–9.0) in the age groups 0–4, 5–9, and 10–14 years, respectively. In young children with a positive TST, not using isoniazid preventive treatment further increased risk of disease (RR, 12.2 [95% CI, 3.8–39.2]).ConclusionsWe present a tool that identifies child household contacts at high risk of TB disease progression based on data collected during contact tracing. In addition to the use of TB preventive therapy for all children exposed at home to TB, those children at highest risk of progressing to TB disease may benefit from more frequent follow-up.

Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion.

Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.

Mycobacterium tuberculosis in solid organ transplant donors and recipients.

Due to impaired immune response, solid organ transplant (SOT) recipients are susceptible to tuberculosis (TB) and its subsequent morbidity and mortality. Current prevention strategies, diagnostic and treatment approach to TB infection in donors and recipients were reviewed in this article. Screening of latent tuberculosis infection (LTBI) in donors and recipients is the cornerstone of TB-preventive strategy in recipients and requires an assessment of TB risk factors, TB-specific immunity testing, and radiographic evaluation. Interferon-gamma release assay has superseded the tuberculin skin test in LTBI evaluation despite its recognized limitations. LTBI treatment should be offered to transplant candidates and living donors before transplantation and donation, respectively. Diagnosis of TB disease can be challenging because of nonspecific clinical presentation in the recipient and is limited by the sensitivity of current diagnostics. The approach to LTBI and TB disease treatment is similar to the general population, but can be challenging because of potential drug interactions and toxicities. The appropriate evaluation of donors and recipients for TB can mitigate posttransplant TB disease. Current approaches to diagnosis and treatment parallels that of immunocompetent hosts. Future research evaluating existing and novel diagnostics and treatment in transplant recipients is needed.

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review.

Infection with Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.

Methylation Status of VDR Gene and its Association with Vitamin D Status and VDR Gene Expression in Pediatric Tuberculosis Disease

ABSTRACT Deficiency in circulatory vitamin D level and vitamin D receptor DNA methylation could be associated with weakened innate immune response and increased susceptibility to tuberculosis (TB) disease in children. Therefore, we aimed to study the effect of vitamin D receptor (VDR) gene methylation on plasma vitamin D level and the expression of the VDR gene in children with active-TB disease. A cross-sectional comparative study was conducted in 43 children with active-TB and 33 healthy control children (HC). The vitamin D level was measured in plasma, while the levels of VDR gene promoter methylation and VDR gene expression were measured in peripheral blood. Children with active-TB showed a significantly lower median vitamin D level than HC [Cases 17.18 ng/mL (IQR, 8.3–18.6 ng/mL); HC 41.34 ng/mL (IQR, 40.2–43.49 ng/mL) (p<0.0001)] and decreased mRNA expression level of VDR gene [Cases 0.51 (IQR, 0.40–0.70); HC 1.06 (IQR, 0.8–1.2) (p<0.0001)] and increased VDR DNA methylation [Cases 75% (IQR, 50–75%); HC 10% (IQR, 10–25%) (p<0.0001)]. The VDR hypermethylation is significantly associated with reduced vitamin D level and decreased expression level of VDR gene. Therefore this inverse association could be involved in the impairment in the VDR mediated cytolytic and antimicrobial effector cell response in pediatric TB disease.

Studies on some immunological profile of patients infected with tuberculosis attending infectious diseases hospital, Kano

The magnitude of the immune response to tuberculosis (TB) infection also involves cell-mediated immunity comprising numerous types of T-cell subsets and this reflects the magnitude of the bacterial load and those with the highest load are at a greater risk of developing TB disease. The study assesses the immunological profile (CD4+, CD8+, CD3+, CD45+) of TB infected individuals with drug sensitive TB (DS-TB) and compares it with that of subjects with Latent Tuberculosis Infection (LTBI) and those with Rifampicin Resistant TB (RR-TB). The study was a cross-sectional study conducted at Infectious Diseases Hospital (IDH), Kano. Two hundred and five (205) subjects participated in the study. Collected sputum samples were subjected to Ziehl-Neelsen (ZN) staining and cultured on Lowenstein Jensen medium for the identification of Mycobacteria tuberculosis. Molecular detection of M. tuberculosis and RR-TB was performed using Xpert® MTB/RIF. Blood samples were also collected and the T-cell counts were determined using flow cytometry. The result of the study indicated that 131 of the studied subjects were males and 74 were females and that majority of them were in the group 14-24years (41.0%), 25-34 years (35.6%) and 35-44 years (13.7%) respectively. Among the DS-TB and RR-TB groups majority were males (70.8% and 66.7% respectively). It was shown that 86.2% and 88.9% of the samples from the DS-TB and RR-TB were AFB positive. However, all the 65 samples of DS-TB and 54 samples of the RR-TB were identified as MTB by culture. All the DS-TB samples were detected as susceptible TB by Xpert® MTB/RIF, and all the samples of the RR-TB were confirmed as rifampicin resistant by the Xpert® MTB/RIF. The study also revealed that the T-cell (CD4+, CD8+, CD3+ and CD45+) counts of the studied subjects varied significantly among the different groups of the study (p&lt;0.05) and that compared to the control and the LTBI groups the DS-TB and the RR-TB groups recorded the lowest counts in the order; Control&gt;LTBI&gt;DS-TB&gt;RR-TB.&#x0D; Key words: Tuberculosis, T-cells counts, Drug susceptible TB, Latent TB, RR-TB.

Regulation of Interferon-γ receptor (IFN-γR) expression in macrophages during Mycobacterium tuberculosis infection.

Interferon-gamma (IFN-γ) is a key cytokine that mediates immunity to tuberculosis (TB). Mycobacterium tuberculosis (M. tb) is known to downregulate the surface expression of IFN-γ receptor (IFN-γR) on macrophages and peripheral blood mononuclear cells (PBMCs) of patients with active TB disease. Many M. tb antigens also downmodulate IFN-γR levels in macrophages when compared with healthy controls. In the current study, we aimed at deciphering key factors involved in M. tb mediated downregulation of IFN-γR levels on macrophage surface. Our data showed that both M. tb H37Rv and M. bovis BCG infections mediate downmodulation of IFN-γR on human macrophages. This downmodulation is regulated at the level of TLR signaling pathway, second messengers such as calcium and cellular kinases i.e. PKC and ERK-MAPK, indicating that fine tuning of calcium response is critical to maintaining IFN-γR levels on macrophage surface. In addition, genes in the calcium and cysteine protease pathways which were previously identified by us to play a negative role during M. tb infection, also regulated IFN-γR expression. Thus, modulations in IFN-γR levels by utilizing host machinery may be a key immune suppressive strategy adopted by the TB pathogen to ensure its persistence and thwart host defense.

MAL adaptor (TIRAP) S180L polymorphism and severity of disease among tuberculosis patients

ObjectiveThough several genetic variants have been recognized to be associated with susceptibility to Tuberculosis (TB) infection and disease, a recent observation on the association of TIRAP C975T (S180L) variants with TB disease severity in mice model prompted us to assess their relevance in humans. In addition, TIRAP variants have also been reported to be associated with varied circulating Interferon-gamma induced protein (IP-10) levels. We investigated the association of TIRAP variants with severity of TB disease and IP-10 production in humans, which may be useful in predicting poor clinical outcome. MethodsCulture positive symptomatic adult pulmonary TB (PTB) patients enrolled between August 2014 and October 2017 were included in this investigation. Allelic discrimination PCR and conventional IP-10 quantification methods were employed for genotyping and IP-10 measurement followed by statistical investigations to analyse patients' variables. ResultsAmong 211 participants, C/C allele was identified in 70% (n = 147); 26% (n = 55) and 4% (n = 9) had C/T and T/T alleles respectively. There was no significant association between TIRAP variants and smear grade, chest-X-ray score, symptom severity score and circulating IP-10 levels. However, significant association was observed between i) circulating IP-10 levels and time to Mycobacterium Growth Indicator Tube (MGIT) culture conversion (p =0.032); ii) smear grade among active TB patients and circulating IP-10 levels (p =0 .032). ConclusionsAlthough mice experiments showed promising results with more severe disease in C/C and T/T individuals, we did not observe any such association in humans.

Examining the Complex Relationship Between Tuberculosis and Other Infectious Diseases in Children.

Millions of children are exposed to tuberculosis (TB) each year, many of which become infected with Mycobacterium tuberculosis. Most children can immunologically contain or eradicate the organism without pathology developing. However, in a minority, the organism overcomes the immunological constraints, proliferates and causes TB disease. Each year a million children develop TB disease, with a quarter dying. While it is known that young children and those with immunodeficiencies are at increased risk of progression from TB infection to TB disease, our understanding of risk factors for this transition is limited. The most immunologically disruptive process that can happen during childhood is infection with another pathogen and yet the impact of co-infections on TB risk is poorly investigated. Many diseases have overlapping geographical distributions to TB and affect similar patient populations. It is therefore likely that infection with viruses, bacteria, fungi and protozoa may impact on the risk of developing TB disease following exposure and infection, although disentangling correlation and causation is challenging. As vaccinations also disrupt immunological pathways, these may also impact on TB risk. In this article we describe the pediatric immune response to M. tuberculosis and then review the existing evidence of the impact of co-infection with other pathogens, as well as vaccination, on the host response to M. tuberculosis. We focus on the impact of other organisms on the risk of TB disease in children, in particularly evaluating if co-infections drive host immune responses in an age-dependent way. We finally propose priorities for future research in this field. An improved understanding of the impact of co-infections on TB could assist in TB control strategies, vaccine development (for TB vaccines or vaccines for other organisms), TB treatment approaches and TB diagnostics.

Genetic susceptibility to Tuberculosis: Interaction between HLA-DQA1 and age of onset

Several genome-wide association studies (GWAS) identified new single nucleotide polymorphisms (SNPs) with susceptibility to Tuberculosis (TB). However, many of them were not replicated across ethnic groups. The cause of this phenomenon of genetic heterogeneity is uncertain. Here, we attempted to replicate and evaluate the mechanism that causes genetic heterogeneity in several putative TB predisposition loci found by previous GWAS, including chromosome 18q, ASAP1, DUSP14, and HLA-DQA1. A Chinese cohort of 1200 TB patients and 1280 population controls were genotyped. The results showed that genetic predisposition to TB might operate in an age-specific manner. While no significant association was found in the whole samples, a SNP of HLA-DQA1, rs9272785, showed suggestive association within the young-onset TB subgroup (onset at 20–40 years of age, N = 396). The results provide support for the hypothesis that there are different pathogenesis mechanisms causing clinical TB disease in different age groups, and that genetics probably play a substantial role only in young-onset TB.