Tuberculosis

Tuberculosis (TB) is a serious infectious disease primarily caused by the bacteriumMycobacterium tuberculosis (M.tb) ^[1]. Historically, TB has been a major cause of death globally, and it continues to be a significant public health challenge, particularly in developing countries.

Biological Basis

M. tuberculosisprimarily infects the lungs, but it can also affect other parts of the body, including the brain, spine, and kidneys. Upon infection, the body’s immune system attempts to contain the bacteria. In many cases, this leads to a latent infection where the bacteria remain dormant without causing symptoms^[1]. However, approximately 5–10% of infected individuals will develop active TB disease, which can be life-threatening if not treated^[1]. The progression from latent infection to active disease is influenced by a complex interplay between the host’s genetic factors and the pathogen^[1]. Numerous genetic and heritability studies have established the critical role of host genetic factors in determining susceptibility to TB ^[1]. Genome-wide association studies (GWAS) have identified specific genetic loci, such as those at 10q26.2, 5q33.3, and 11p13, that are associated with resistance or susceptibility to M. tuberculosisinfection^[2].

Clinical Relevance

Diagnosing TB can be challenging, and treatment typically involves a prolonged course of multiple antibiotics. A significant concern in TB treatment is the development of drug resistance, which complicates management and increases mortality. Additionally, anti-tuberculosis drugs can sometimes lead to adverse effects, such as liver toxicity^[3]. TB manifests in various forms, including pulmonary tuberculosis, which affects the lungs, and more severe extrapulmonary forms like tuberculous meningitis, which impacts the brain and spinal cord^[4]. Genetic research plays a crucial role in understanding individual susceptibility to different forms of TB and their treatment outcomes. Studies have explored risk prediction models for pulmonary tuberculosis using both genetic and conventional risk factors^[5], and have investigated genetic susceptibility to severe forms like tuberculous meningitis ^[4]. Genetic studies have also been conducted across diverse populations, including Western Chinese Han and Tibetan, Korean, and South African Coloured populations, to identify ancestry-specific risk factors ^[6].

Social Importance

Tuberculosis remains a major global health burden. The World Health Organization (WHO) reported an estimated 10 million TB cases and 1.5 million deaths in 2019^[1]. The disease disproportionately affects populations in low- to middle-income countries, where incidence rates can be significantly higher, such as 615 per 100,000 in South Africa^[1]. The limitations of currently available therapies and vaccines underscore the ongoing need for research into the genetics of TB susceptibility and resistance. Understanding the genetic basis of TB can lead to better diagnostic tools, more effective treatments, and improved vaccine strategies, ultimately contributing to global efforts to control and eradicate this ancient disease^[7].

Limitations

Methodological and Statistical Constraints

Genome-wide association studies (GWAS) for tuberculosis susceptibility have often been limited by insufficient sample sizes, which can reduce the statistical power needed to robustly identify genetic associations^[8]. While some studies have successfully validated their findings in independent populations ^[5], consistently replicating all initial discoveries remains a challenge, potentially leading to inflated effect sizes for initial findings or gaps in confirming their broader significance ^[8]. The analytical approaches employed also present constraints, particularly in meta-analyses where fixed-effects models are used to combine results. High heterogeneity across studies can complicate the interpretation of combined association results ^[8]. Furthermore, establishing robust genetic associations requires meeting stringent genome-wide significance thresholds, typically set at P = 5 × 10−8, which can be difficult to achieve without very large cohorts ^[2].

Population Diversity and Phenotypic Heterogeneity

A significant limitation in understanding tuberculosis genetics is the variability across human populations. While multi-ancestry meta-analyses aim to uncover shared genetic architecture^[4], specific genetic risk factors can be ancestry-dependent ^[8], requiring sophisticated approaches like local ancestry adjusted analyses to accurately capture susceptibility loci ^[1]. This diversity implies that findings from one population may not be fully generalizable to others, hindering a comprehensive cross-population understanding ^[9]. The definition and measurement of the tuberculosis phenotype also pose challenges. Tuberculosis manifests in various forms, such as pulmonary tuberculosis or more severe presentations like tuberculous meningitis^[5], ^[10], and genetic susceptibility may differ for these distinct clinical outcomes. Additionally, sex-stratified analyses, while crucial for identifying sex-specific genetic influences, can suffer from reduced statistical power, especially when analyzing haploid genotypes in males, making it difficult to fully elucidate how identified variants impact susceptibility across sexes ^[11].

Environmental Confounding and Unexplained Heritability

The genetic landscape of tuberculosis susceptibility is further complicated by influential environmental and gene-environment interactions. Factors such as socio-economic conditions, smoking status, and co-occurring acute infections are significant confounders that can modulate an individual’s risk of developing active tuberculosis^[8]. Accurately accounting for these complex non-genetic influences is essential but challenging, as they can mask or modify the observable genetic effects. Despite evidence from twin studies highlighting a strong genetic component to tuberculosis susceptibility^[8], a substantial portion of this heritability remains unexplained by identified genetic variants. This “missing heritability” suggests that current studies may not fully capture all contributing genetic factors, which could include rare variants, complex epistatic interactions, or epigenetic modifications, thus indicating a continuing need for broader and more comprehensive investigations ^[12].

Variants

Key Variants

RS ID	Gene	Related Traits
rs532003101	SERPINA9 - SERPINA12	tuberculosis
rs7971813	PPFIA2-AS1, PPFIA2	tuberculosis
rs564904244	CDC14C - DDX43P2	tuberculosis
rs191653573	HNRNPA1P47 - LINC01821	tuberculosis
rs1495741	NAT2 - PSD3	triglyceride measurement total cholesterol measurement urinary bladder carcinoma tuberculosis CDHR2/MME protein level ratio in blood
rs17175227	SMOC1 - SLC8A3	tuberculosis
rs75609205	MYT1L	tuberculosis
rs41553512	HLA-DRB5	tuberculosis
rs12294076	DYNC2H1	tuberculosis
rs142513793	ZNF630	tuberculosis

Immune Response and Antigen Presentation

The Human Leukocyte Antigen (HLA) region plays a critical role in the immune system, particularly in presenting antigens to T-cells, which is crucial for initiating an effective immune response against pathogens like Mycobacterium tuberculosis. The variant rs41553512 is located within or near the HLA-DRB5gene, a component of the HLA class II complex. HLA class II molecules are expressed on antigen-presenting cells and are vital for recognizing extracellular pathogens. Variations in HLA genes, including HLA-DRB5, can alter the efficiency of antigen presentation, thereby influencing an individual’s susceptibility or resistance to tuberculosis^[6]. Studies have consistently shown that specific HLA class II sequence variants, such as alleles of HLA-DRB1*04, are associated with the risk of pulmonary tuberculosis in diverse populations, highlighting their significant impact on the host’s ability to mount a protective immune response^[13]. Therefore, rs41553512 may influence TB susceptibility by subtly modifying the function or expression of HLA-DRB5, affecting how the immune system perceives and responds to the tuberculosis bacterium.

Neuronal Development and Cellular Regulation

The MYT1L gene, associated with the variant rs75609205 , encodes a transcription factor primarily known for its essential role in neuronal differentiation and development. While its direct involvement in tuberculosis pathogenesis is not fully understood, MYT1L’s influence on cellular processes could extend to broader physiological functions, including those relevant to immune regulation or tissue repair, which are critical during infection. Genetic studies have identified suggestive loci for tuberculosis susceptibility within the intron regions of genes such as MYT1L, indicating potential regulatory effects of these variants on gene expression^[6]. Such variants, even if located in non-coding regions, might affect gene splicing, stability, or the binding of regulatory proteins, indirectly influencing host responses to infection. The identification of rare variants, including those in genes like MYT1L, contributes to understanding the complex genetic landscape that predisposes individuals to infectious diseases like tuberculosis^[14].

Diverse Cellular Pathways and Disease Susceptibility

Numerous other genetic variants are also implicated in the complex interplay of human genetics and disease susceptibility. For instance,rs532003101 involves genes SERPINA9 and SERPINA12, which belong to the serpin family of protease inhibitors, crucial for regulating inflammatory and immune responses. Similarly, rs7971813 is associated with PPFIA2-AS1 and PPFIA2, genes involved in cell adhesion and synaptic organization, processes that can affect cellular communication and tissue integrity during infection.CDC14C and DDX43P2, linked to rs564904244 , play roles in cell cycle regulation and RNA processing, respectively, fundamental cellular mechanisms that can be altered during pathogen invasion. Variants like rs191653573 near HNRNPA1P47 and LINC01821 may impact RNA binding and long non-coding RNA functions, which are emerging regulators of gene expression. Furthermore, rs1495741 is associated with NAT2 and PSD3, where NAT2 is known for drug metabolism and PSD3 for its role in cellular signaling. The variant rs17175227 involves SMOC1 and SLC8A3, genes related to extracellular matrix organization and calcium transport, both vital for cell structure and signaling. Lastly, rs12294076 is linked to DYNC2H1, a gene encoding a motor protein involved in intracellular transport, and rs142513793 is associated with ZNF630, a zinc finger protein that likely functions in gene regulation. While the precise mechanisms by which each of these specific variants influences tuberculosis susceptibility are still under investigation, these diverse genetic factors collectively highlight how perturbations in various fundamental cellular pathways, from immune regulation and metabolism to cell structure and signaling, can contribute to an individual’s overall genetic predisposition to infectious diseases^[15].

Definition and Scope of Tuberculosis

Tuberculosis (TB) is a chronic infectious disease primarily caused by the bacteriumMycobacterium tuberculosis (Mtb) ^[7]. This pathogen is responsible for a significant global health burden, with estimates indicating that approximately a quarter of the world’s population is infected ^[6]. The conceptual framework of TB encompasses not only active symptomatic disease but also latent infection, where the bacteria are present in the body without causing overt symptoms.

The disease manifests in various forms, most commonly affecting the respiratory system, a condition known as pulmonary tuberculosis^[5]. However, Mtb can disseminate beyond the lungs, leading to extrapulmonary tuberculosis in various organs. For instance, tuberculous meningitis is a severe manifestation affecting the central nervous system, which can have significant clinical consequences, including mortality^[4]. Understanding the full scope of TB requires acknowledging both the active disease state and the quiescent, latent infection, which can be detected through specific immunological responses.

Clinical Classification and Manifestations

Tuberculosis is systematically classified based on the anatomical site of infection and the activity status of the disease. The most prevalent form is pulmonary tuberculosis (PTB), characterized by symptoms such as chest pain, fever, and weight loss, often identifiable through characteristic findings on chest X-rays^[16]. Extrapulmonary forms, such as tuberculous meningitis, involve other body systems and represent distinct clinical entities ^[4].

Further classification distinguishes between active TB disease, where individuals are symptomatic and potentially infectious, and latent tuberculosis infection (LTBI), where theMtb bacteria are present but dormant, with the individual remaining asymptomatic and non-infectious ^[17]. Severity gradations in active disease are assessed through various clinical and laboratory indicators, including the presence of lung cavities, elevated systemic inflammatory markers like erythrocyte sedimentation rate (ESR), and the quantity of mycobacteria observed in sputum smears^[15]. These classifications are fundamental for tailoring treatment regimens, implementing public health control measures, and for research studies that analyze genetic susceptibility by comparing patient cohorts against healthy controls ^[6].

Diagnostic and Measurement Approaches

The diagnosis of active tuberculosis relies on a comprehensive set of clinical, microbiological, and radiological criteria. Clinically, a presumptive diagnosis is often made based on characteristic symptoms such as persistent cough, fever, and unexplained weight loss^[16]. Microbiological confirmation is crucial and typically involves the microscopic detection of acid-fast bacilli (AFB) in sputum smears, followed by the culture of Mycobacterium tuberculosis from sputum samples ^[16]. Radiological imaging, particularly chest X-rays (CXR), provides essential diagnostic information by revealing typical patterns of pulmonary involvement, such as infiltrates or cavitations ^[16].

Beyond active disease, immunological tests are used to detectMycobacterium tuberculosisinfection, particularly latent forms. The Tuberculin Skin Test (TST) is a key measurement, with a positive result generally defined as an induration of 5mm or more, especially in high-risk groups^[17]. Research criteria for diagnosing TB often involve strict operational definitions, requiring confirmed Mtb sputum culture, AFB positivity, and characteristic CXR findings, while excluding individuals already undergoing anti-TB treatment ^[15]. Emerging measurement approaches include the investigation of plasma cytokine levels (e.g., IL-6, sIL-2R, TNF-α) and ESR as potential biomarkers^[15], and genetic markers, such as specific genotypes like LTA4H, are being studied for their prognostic value in predicting outcomes like mortality in severe forms such as tuberculous meningitis^[4].

Signs and Symptoms

Tuberculosis (TB) manifests through a range of clinical presentations, from typical respiratory symptoms to severe extra-pulmonary forms, with diagnosis relying on a combination of subjective and objective measures. The disease exhibits significant heterogeneity in its presentation and progression, influenced by individual and demographic factors. Understanding these diverse patterns and their assessment is crucial for accurate diagnosis and effective management.

Typical Clinical Manifestations and Initial Assessment

The most common signs and symptoms of tuberculosis often include persistent chest pain, fever, and unexplained weight loss^[16]. Pulmonary tuberculosis, affecting the lungs, is a prevalent form of the disease. Initial diagnostic assessment typically involves identifying acid-fast bacilli in sputum smears, which confirms the presence of theMycobacterium tuberculosis pathogen ^[16]. Complementary to this, chest X-rays (CXR) are a fundamental diagnostic tool, revealing characteristic patterns of pulmonary TB, such as the presence of cavities in the lung ^[16]. These primary clinical and imaging findings are critical for establishing a definitive diagnosis and are often the first indicators prompting further investigation ^[16].

Diverse Phenotypes and Objective Diagnostic Markers

Beyond the typical pulmonary presentation, tuberculosis can manifest with diverse phenotypes, including severe forms like tuberculous meningitis^[4]. To characterize these varied presentations and assess disease activity, several objective diagnostic tools and biomarkers are employed. These include measuring plasma levels of cytokines, such as IL-6, sIL-2R, and TNF-α, as well as evaluating the erythrocyte sedimentation rate (ESR)^[15]. Routine inflammatory markers are also assessed to gauge the systemic response to infection^[4]. The tuberculin skin test (TST) reactivity is another important assessment method, particularly in specific populations like HIV-positive individuals residing in hyper-endemic regions ^[17]. These objective measures provide valuable insights into the disease’s severity and help in identifying prognostic indicators.

Heterogeneity in Presentation and Prognostic Indicators

The clinical presentation and susceptibility to tuberculosis are marked by significant inter-individual variation and heterogeneity across different populations, including adult Korean, Western Chinese Han and Tibetan, and South African Coloured populations^[5]. Research has also explored sex differences in TB susceptibility through sex-stratified analyses ^[4]. The diagnostic significance of combining clinical observations with objective findings is paramount; specific signs, symptoms, and CXR results, such as the presence of lung cavities and mycobacteria in sputum, are crucial for diagnosis and serve as important prognostic indicators ^[15]. Furthermore, in severe forms like tuberculous meningitis, clinical parameters, routine inflammatory markers, and genetic factors are recognized as key predictors of mortality, highlighting the complex interplay of host and pathogen factors in determining disease outcome^[4].

Causes

Tuberculosis (TB), caused by the bacteriumMycobacterium tuberculosis(Mtb), is a complex infectious disease resulting from a multifactorial interaction between the host, the pathogen, and the environment ;^[18]; ^[5]. An estimated one-quarter of the global population shows immunological evidence of prior M.tb exposure, yet only a subset, approximately 5-10% of infected individuals, will progress to develop active TB disease, while the majority remain asymptomatic^[4]; ^[1]; ^[18].

Pathogenesis and Disease Manifestations

Tuberculosis is characterized by a diverse range of pathophysiological processes, beginning with initial exposure and infection. After exposure toM. tuberculosis, most individuals become infected, but the development of clinical disease is highly variable^[18]. The disease can manifest in different forms, most commonly as pulmonary tuberculosis (PTB), affecting the lungs. However, TB can also present as extra-pulmonary disease, such as tuberculous meningitis, which affects the central nervous system^[18]; ^[4].

The timing and presentation of active disease also vary. Some infected individuals, particularly young children, may develop “primary” TB with extra-pulmonary manifestations within two years of initial infection^[18]. In contrast, other individuals may develop clinical TB much later in life, typically as pulmonary TB, which can arise from the reactivation of a latent, previously acquired infection or from a new infectious episode^[18]. These variations highlight the dynamic nature of TB pathogenesis and the interplay between host factors and pathogen activity.

Host Immune Response and Cellular Mechanisms

The host’s immune system is central to controlling Mycobacterium tuberculosisinfection, relying on a complex network of cellular functions and signaling pathways. Human host immunity to mycobacteria involves intricate mechanisms aimed at containing the pathogen, and disruptions in these homeostatic immune responses can contribute to disease progression^[19]; ^[20]. Effective cellular functions and regulatory networks are crucial for mounting a protective immune response, preventing the transition from latent infection to active disease.

Key biomolecules, including specific proteins, enzymes, and transcription factors, mediate these cellular defenses. For example, single-gene inborn errors affecting interferon-gamma (IFN-γ) immunity have been identified as critical factors in the control of childhood TB, underscoring the importance of this specific signaling pathway ^[18]. Furthermore, candidate genes involved in innate immunity are actively investigated for their role in susceptibility to severe forms of the disease, such as tuberculous meningitis, emphasizing the foundational role of early immune responses in disease outcome^[4].

Genetic Susceptibility to Tuberculosis

Human genetic factors significantly contribute to the observed variability in individual responses to M. tuberculosisinfection and the susceptibility to developing active disease^[18]; ^[1]. Heritability studies have firmly established the influence of host genetic factors on TB susceptibility, indicating that an individual’s genetic makeup can predispose them to different disease trajectories^[1]. Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic loci associated with either resistance or susceptibility to TB across diverse populations.

For instance, a notable locus at 10q26.2 has been identified as being associated with resistance to M. tuberculosisinfection^[2]. Conversely, common genetic variants located at chromosome 11p13 have been linked to increased susceptibility to tuberculosis^[20]. These findings demonstrate that specific genomic regions, containing genes or regulatory elements, play a crucial role in modulating an individual’s intrinsic defense mechanisms and overall response to the pathogen.

Molecular Regulation and Biomolecular Impact

Beyond direct genetic variants, the molecular regulation of gene expression and epigenetic modifications significantly influence the host’s interaction with M. tuberculosis. Research indicates that associated genetic variants often overlap with critical regulatory regions, such as histone marks identified through projects like ENCODE, suggesting that alterations in chromatin structure and gene regulation can profoundly impact disease susceptibility^[2]. These intricate regulatory networks fine-tune cellular functions and metabolic processes that are crucial for mounting an effective and sustained immune response against the pathogen.

Key biomolecules, including specific enzymes and proteins, also play a direct role in the pathophysiological processes of TB and can influence disease severity. For example, the LTA4H genotype has been identified as a predictor of mortality in patients with tuberculous meningitis, illustrating how variations in a single gene can affect severe clinical outcomes^[4]. Additionally, the chromosome 5q31.1 locus, which associates with tuberculin skin test reactivity, further underscores the intricate interplay of genetic factors and immune responses at a molecular level, reflecting the complex biological landscape of tuberculosis^[17].

Population Studies

Population studies on tuberculosis (TB) are crucial for understanding the disease’s epidemiology, identifying risk factors, and uncovering genetic predispositions across diverse human populations. These large-scale investigations employ various methodologies to track incidence, prevalence, and host-pathogen interactions, providing insights essential for public health strategies and personalized medicine.

Genetic Determinants of Tuberculosis Susceptibility and Resistance

Population studies have extensively explored the genetic underpinnings of tuberculosis (TB) susceptibility and resistance, employing large-scale genomic approaches like Genome-Wide Association Studies (GWAS) across diverse ethnic groups. These studies aim to identify specific genetic variants that influence an individual’s likelihood of developing TB or resisting infection. For instance, a locus at 10q26.2 was identified as contributing to resistance toMycobacterium tuberculosisinfection through a GWAS conducted in three distinct populations, highlighting potential shared genetic mechanisms^[2]. Similarly, common variants located at 11p13 have been consistently associated with TB susceptibility, indicating their broader role in host defense mechanisms ^[20]. Further research utilized local ancestry adjusted allelic association analysis to robustly capture additional TB susceptibility loci, particularly relevant in populations with mixed ancestries ^[1].

Cross-population comparisons have revealed both shared and unique genetic architectures influencing TB. A meta-analysis across multiple ancestries identified shared genetic susceptibility loci for TB, while also providing subgroup-specific insights for Asian and African populations ^[4]. Distinct population groups, such as the western Chinese Han and Tibetan populations, have been the focus of GWAS studies to uncover population-specific genetic associations with TB, involving analysis of millions of single nucleotide polymorphisms (SNPs) in thousands of patients and controls^[6]. These investigations also identified specific loci, such as 5q31.1, associated with tuberculin skin test reactivity in HIV-positive individuals residing in TB hyper-endemic regions of East Africa, and a locus at 5q33.3 that confers resistance in highly susceptible individuals, underscoring the complex interplay of genetic background and environmental factors in TB outcomes ^[17].

Epidemiological Patterns and Risk Prediction in Specific Populations

Large-scale cohort studies provide crucial insights into temporal patterns and risk factors for tuberculosis development within specific populations. In an adult Korean population, research focused on developing risk prediction models for pulmonary tuberculosis by integrating both genetic and conventional risk factors^[5]. Such studies leverage longitudinal data to understand how various factors, including demographic characteristics and lifestyle, contribute to TB incidence and progression over time. The identification of these risk factors is vital for public health interventions and targeted screening programs.

Epidemiological associations also extend to specific forms of the disease and co-morbidities. For instance, genetic susceptibility to tuberculous meningitis (TBM) has been investigated, with studies evaluating the LTA4H genotype alongside clinical and inflammatory markers as predictors of mortality among TBM patients^[4]. Additionally, population studies have explored TB susceptibility in vulnerable groups, such as HIV-positive individuals in hyper-endemic regions of East Africa, where genetic loci influencing tuberculin skin test reactivity were identified, highlighting the complex interaction between host genetics, co-infection, and disease manifestation^[17]. These findings underscore the importance of considering specific population contexts and co-existing health conditions when assessing TB risk and outcomes.

Methodological Approaches and Considerations in Tuberculosis Population Studies

The rigorous methodologies employed in tuberculosis population studies are critical for generating robust and generalizable findings, though they also present inherent limitations. Genome-Wide Association Studies (GWAS) are a cornerstone, involving the analysis of millions of genetic markers across thousands of individuals, such as the study on western Chinese Han and Tibetan populations that retained over 4 million SNPs in more than 3,000 participants for logistic regression analysis^[6]. These large sample sizes are essential for detecting genetic associations with sufficient statistical power, particularly for complex traits like TB susceptibility. However, the representativeness of these samples and the generalizability of findings across diverse global populations remain key considerations, often addressed through multi-ethnic and multi-ancestry meta-analyses ^[4].

Further methodological refinements include sex-stratified analyses, which acknowledge potential sex-specific genetic influences on TB susceptibility, although such approaches can face power limitations when analyzing haploid genotypes or smaller subgroups ^[4]. Beyond susceptibility, GWAS has also been applied to investigate host genetic factors influencing outcomes such as anti-tuberculosis drug-induced liver toxicity, utilizing replication studies to confirm initial associations^[3]. While these designs are powerful, careful consideration of population stratification, environmental confounding, and the potential for false positives is crucial, ensuring that identified genetic associations are biologically meaningful and clinically relevant across different demographic and geographic contexts ^[6].

Pharmacogenetics

Genetic Predisposition to Anti-Tuberculosis Drug-Induced Liver Injury

A genome-wide association study (GWAS), followed by a replication study, has been conducted to investigate genetic factors contributing to anti-tuberculosis drug-induced liver toxicity^[3]. This research identifies specific genetic variants that may predispose individuals to hepatotoxicity, a common and serious adverse drug reaction during tuberculosis treatment^[3]. Understanding these genetic associations is crucial for elucidating the underlying mechanisms of drug-induced liver injury and for predicting individual susceptibility ^[3]. While specific clinical guidelines are not detailed, such genetic insights hold promise for the development of personalized treatment approaches, potentially enabling clinicians to identify patients at higher risk of adverse reactions and adjust therapeutic regimens accordingly ^[3].

Frequently Asked Questions About Tuberculosis

These questions address the most important and specific aspects of tuberculosis based on current genetic research.

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1. Why did my friend get TB, but I didn’t get sick?

Your immune system and genetic makeup play a critical role in how your body responds to M. tuberculosis. Even with similar exposure, individual differences in host genetic factors determine who becomes susceptible to the infection and who can resist it. Genome-wide studies have identified specific genetic regions linked to resistance.

2. If I’m exposed to TB, will I definitely get sick?

No, not necessarily. While you might become infected, your immune system often contains the bacteria, leading to a latent infection without symptoms. Only about 5–10% of infected individuals develop active TB disease, and your unique genetic factors significantly influence whether you progress to active illness.

3. Is my family history linked to my TB risk?

Yes, absolutely. Numerous genetic and heritability studies have established that host genetic factors play a critical role in determining your susceptibility to TB. These genetic predispositions can run in families, meaning if TB is common in your family history, you might have an inherited increased risk.

4. Could my genetics make my TB attack my brain?

Yes, your genetics can influence the form and severity of TB you might develop. Research shows that specific genetic susceptibilities exist for more severe forms, such as tuberculous meningitis, which affects the brain and spinal cord. Your genetic profile can steer the disease towards affecting particular parts of your body.

5. Why do TB medicines cause liver problems for some, but not me?

Your genetic makeup influences how your body processes medications, including anti-tuberculosis drugs. Some people have genetic variations that make them more prone to adverse effects, such as liver toxicity, when taking these drugs. Genetic studies are helping to understand these individual differences in drug response.

6. Does my family’s ethnic background change my TB risk?

Yes, it can. Genetic risk factors for TB are not uniform across all human populations; some are ancestry-dependent. Studies in diverse groups, like Western Chinese Han, Tibetan, Korean, and South African Coloured populations, have identified specific genetic factors unique to those ancestries that influence TB risk.

7. Can I prevent TB even if my family has it?

While your genetic background certainly plays a role in susceptibility, it’s not the only factor. The progression of TB is a complex interplay between your host genetic factors and the pathogen, as well as environmental influences. Maintaining a strong immune system and avoiding exposure are still crucial preventative measures.

8. Could a genetic test tell me if I’m at high TB risk?

In the future, yes, such tests could become more common. Current genetic research, including genome-wide association studies, has already identified specific genetic loci like 10q26.2, 5q33.3, and 11p13 associated with TB susceptibility. Understanding your genetic profile could eventually help predict your individual risk and inform personalized prevention strategies.

9. Will my kids inherit my family’s TB susceptibility?

Yes, it’s possible. The genetic factors that influence susceptibility to TB are heritable, meaning they can be passed down from parents to children. If there’s a history of TB susceptibility in your family, your children may inherit some of those genetic predispositions.

10. Why do some people never get TB, even when exposed?

Some individuals possess specific genetic factors that confer a degree of natural resistance to M. tuberculosisinfection. Their immune systems might be more effective at containing or eliminating the bacteria before it can establish a foothold or cause active disease, even after significant exposure.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[2] Quistrebert, J et al. (2021). Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations. PLoS Genet, 17(3), e1009392.

[3] Petros, Z., et al. “Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity.”BMC Genomics, 2016, PMID: 27671213.

[4] Schurz, H., et al. “Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture.”eLife, vol. 13, 2024, RP93184. DOI: 10.7554/eLife.93184.

[5] Hong, E. P., et al. “Risk prediction of pulmonary tuberculosis using genetic and conventional risk factors in adult Korean population.”PLoS One, vol. 12, no. 3, 2017, e0174148.

[6] Bai, H et al. (2023). Genome-wide association study of tuberculosis in the western Chinese Han and Tibetan population. MedComm (2020), 4(2), e250.

[7] Zumla A et al. Tuberculosis. N Engl J Med. 2013;368(8):745-755.

[8] Chimusa, E. R., et al. “Genome-wide association study of ancestry-specific TB risk in the South African Coloured population.” Human Molecular Genetics, vol. 23, no. 3, 2014, pp. 782–790.

[9] Sakaue, S., et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics, vol. 53, no. 10, 2021, pp. 1415-1424.

[10] Schurz H et al. Deciphering Genetic Susceptibility to Tuberculous Meningitis. Front Neurol, 2022;13:820168.

[11] Schurz, H et al. (2019). A Sex-Stratified Genome-Wide Association Study of Tuberculosis Using a Multi-Ethnic Genotyping Array. Front Genet, 9, 678.

[12] Tam, V., et al. “Benefits and limitations of genome-wide association studies.” Nature Reviews Genetics, vol. 20, no. 8, 2019, pp. 467-484.

[13] Phelan, J., et al. “Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease.”Nat Commun, vol. 14, no. 1, 2023, p. 574.

[14] Gelemanovic, A., et al. “Genome-Wide Meta-Analysis Identifies Multiple Novel Rare Variants to Predict Common Human Infectious Diseases Risk.” Int J Mol Sci, vol. 24, no. 7006, 2023.

[15] Zheng, R et al. (2018). Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese. Nat Commun, 9(1), 4059.

[16] Curtis, J et al. (2015). Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet, 47(5), 523-528.

[17] Sobota, Rebecca S., et al. “A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa.”PLoS Genetics, vol. 13, no. 6, 2017, e1006824. DOI: 10.1371/journal.pgen.1006824.

[18] Grant, Adrie¨nna V., et al. “A genome-wide association study of pulmonary tuberculosis in Morocco.”Human Genetics, vol. 135, no. 4, 2016, pp. 433-442.

[19] Ottenhoff, Tom H. M., et al. “Control of human host immunity to mycobacteria.” Tuberculosis, vol. 85, no. 1-2, 2005, pp. 53-64.

[20] Thye, T., et al. “Common variants at 11p13 are associated with susceptibility to tuberculosis.”Nature Genetics, vol. 44, no. 3, 2012, pp. 257–259.