|Year : 2019 | Volume
| Issue : 3 | Page : 244-252
Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis
Former Addl. DHS, Kerala Health Services, Palakkad, Kerala, India
|Date of Web Publication||24-Apr-2019|
Dr. P P Aravindan
Dr. P P Aravindan, Sajitha Nivas, Hussain Colony, West Fort Road, Palakkad - 678 001, Kerala
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Objective: Tuberculosis (TB), the leading cause of morbidity and mortality by a single infectious agent, Mycobacterium tuberculosis, is still a major health problem in the world. To date, many studies have shown evidence of association between host genetic polymorphisms and TB susceptibility, including chemokine (C-C motif) ligand 2 (CCL-2)/monocyte chemoattractant protein1 (MCP-1), natural resistance-associated macrophage protein 1 (NRAMP-1)/solute carrier protein 11A1 (SLC11A1), Immunity-related GTPase family M protein (IRGMI), interleukin (IL)-8, toll-like receptor (TLR), and nucleotide-binding oligomerization domain containing protein-2 (NOD-2) genes. Most of these genes participate in immune response, and their polymorphism can alter immunity and lead to genetic susceptibility to TB. Materials and Methods: This is a special article compiled with reference to various case-control studies, meta-analysis, and other research work on different genes and TB. The genes selected and a number of studies from different countries and ethnic groups for this article are shown below. The genes selected for the study are: NRAMP-1 (SLC11 A1), Vitamin D receptor, low molecular weight polypeptide/transporter with antigen processing, CCL-2/MCP-1, IRGM-1, IL-1, IL-8, IL-10, IL-12, TLR, NOD-2, human leukocyte antigen, mannose-binding lectin, major histocompatibility complex, tumor necrosis factor, P2X 7, epiregulin, SP110, and interferon gamma (IFN-gamma). Results: Genetic polymorphisms in different genes showed variable levels of significance in relation to TB. All these were proved by the researchers using appropriate statistical methods and tools. Conclusions: Based on different research works across the world, there is sufficient evidence to prove that TB is a genetically primed and determined infectious disease caused by M. tuberculosis and the genetic polymorphism is the mechanism that leads to progression from infection to TB disease. Why only 10–15% of the people infected with M. tuberculosis progress toward TB disease has continued to be an unresolved debate. Hence, for provoking thoughts and encouraging more research in the field of genetics and TB I formulated hypothesis and algorithms, and theory. Genetic susceptibility to TB has been substantiated based on the extensive literature review and the research findings that are well narrated.
Keywords: Algorithm, genes, genetic polymorphism, theory, tuberculosis
|How to cite this article:|
Aravindan P P. Host genetics and tuberculosis: Theory of genetic polymorphism and tuberculosis. Lung India 2019;36:244-52
| Introduction|| |
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Patients suffering from smear-positive pulmonary TB (PTB) constitute the most important source of infection. The infection occurs most commonly through droplet nuclei generated by coughing, sneezing, etc. and inhaled via the respiratory route. The chances of getting infected depend on the duration, frequency of exposures, and the immune status of an individual.
According to the annual report on global control of TB from the World Health Organization, about 9.4 million incident cases and 14 million prevalent cases occurred in 2009. Approximately 1.7 million people died of TB, including 0.38 million deaths among human immunodeficiency virus (HIV)-positive people and most cases were in the Southeast Asia, Africa, and Western Pacific regions(35%, 30%, and 20%, respectively).
Entry and establishment of bacilli in the human body constitute infection. It usually takes 6–8 weeks for the establishment and manifestation of infection. Lung TB spreads through droplets that enter via air breathing to lung alveoli, which evoke an inflammation response through accumulation of macrophages and neutrophils, which then migrate to regional lymph nodes to form a Primary Complex. The sub pleural lung lesion, lymphangitis, and hilar adenopathy together constitute a “primary complex.” In most cases, the host's immune defenses overcome the primary infection that generally passes unnoticed.
Secondary bacillary multiplication that occurs at the regional lymph nodes causes bacillemia resulting in the implantation of seedlings of bacilli in different parts of the body. In few cases, the infections may develop into progressive primary forms of TB diseases such as meningitis and miliary TB. However, in a majority of the cases, the multiplication of the bacilli is contained by the host defense mechanism.
All those who get infected do not necessarily develop TB diseases. The lifetime risk of progression to the disease among those infected with TB is 10–15% that gets increased to 10% per year among those coinfected with HIV. Other determinants such as diabetes mellitus, the smoking of tobacco products, malnutrition, and alcohol abuse also increase the risk of progression from infection to TB disease.
It is well-known that host genetic susceptibility, together with bacterial strains and environmental factors, play an important role in determining TB predisposition and drug response. Only about 10% of the infected individuals develop the clinical disease while most infected people carry the bacteria without overt symptoms., To date, many studies have shown the evidence of an association between host genetic polymorphisms and TB susceptibility including chemokine (C-C motif) ligand-2 (CCL-2)/monocyte chemoattractant protein 1 (MCP-1), natural resistance-associated macrophage protein 1 (NRAMP-1)/solute carrier protein 11A1 (SLC11A1), IRGMI, interleukin (IL) 8, toll-like receptor (TLR), and nucleotide-binding oligomerization domain-containing protein 2 (NOD 2) genes.,,,,,
Most of these genes participate in immune response, and their polymorphism can alter immunity and lead to genetic susceptibility to TB.
In humans, NRAMP gene is expressed in macrophages, lymphocytes, and lung tissue. The gene encodes a protein that functions as a divalent ion channel. Fe++ ion can inhibit the growth of M. tuberculosis. When a mutation of NRAMP-1 gene yields a nonfunctional NRAMP-1 protein, there is an inhibition on the intracellular killing mechanism of M. tuberculosis in macrophages. Bellamy et al. have reported in Gambia that polymorphism in 5'(GT)nINT4, D543, and 3'UTR of NRAMP1 enhance susceptibility to M. tuberculosis.
Many studies have revealed that of the people who are infected with TB, many are considered less susceptible due to the genetic and environment factors., A study from Poland and another study from Indonesia found that INT 4 polymorphism is not associated with TB infection but is strongly correlated with autoimmunity; however, both D'543N and 3'UTR polymorphisms are associated with susceptibility to TB infection. Assessment of the contribution of the genetics of host resistance to human TB is one of the longstanding challenges of human genetics research, and TB has been considered as a complex disease with strong genetic components. There are several studies that provide strong data in support of genetic factors being involved in TB susceptibility.
Host genetic factors such as human leukocyte antigen (HLA) and non-HLA genes that are associated with the susceptibility to TB, have been studied using various methods such as case–control studies, candidate gene approach, family-based and genome-wide linkage studies and will serve as genetic markers to predispose or predetermine development of the disease.
Similarly, susceptibilityto M. tuberculosis also has genetic variation. HLA studies carried out in the Asian region, especially in India, demonstrated the association of HLA-DR2 and HLA-DQ1 antigens with susceptibility to PTB. Various diallelic polymorphisms have been identified in the Vitamin D receptor (VDR) gene and these polymorphic variants have been demonstrated to be associated with the TB susceptibility or resistance.
The human NRAMP-1, renamed as SLC11A1-solute carrier family 11, member 1 gene has several polymorphisms. An association has been found between NRAMP-1 gene and TB susceptibility in populations as diverse as the West Africans, Koreans, and Japanese., A case–control study conducted in the Gambia showed that NRAMP-1 polymorphisms were significantly associated with TB susceptibility.
There is substantial evidence from studies on racial variations in susceptibility to TB that a complex interaction of genetic and environmental factors causes the development of clinical TB.,
M. tuberculosis is a facultative intracellular pathogen that utilizes the macrophage as its host cell. Resistance to M. tuberculosis involves a complex interaction between the bacteria and the host immune system. Cytokines are believed to play a key role in mycobacterial resistance. Macrophages are activated by interferon-gamma (IFN-gamma), tumor necrosis factor (TNF) alpha, Vitamin D, and IL-6.
In a well-matched case–control study for candidate gene, several candidate gene polymorphisms have been typed, and associations have been detected for NRAMP-1VDR and mannose-binding lectin (MBL) gene variants.,,
Results of the case–control study demonstrates that although NRAMP-1 gene is not the sole determinant of host TB susceptibility; it is an important mycobacteria susceptibility gene in humans as well as in mice.
Epidemiological evidence suggests a link between Vitamin D deficiency and susceptibility to TB, and Vitamin D has shown to have beneficial effect in cutaneous TB. Vitamin D is an important immune regulatory hormone. The active metabolite of Vitamin D; 1,25-dihydroxy Vitamin D3 (1,25-dihydroxy cholecalciferol), activates monocytes, stimulates cell-mediated immunity, and suppresses lymphocyte proliferation, immunoglobulin production, and cytokine synthesis.
MBL is a calcium-dependent serum lectin. It interacts with the immune system by acting as an opsonin to promote phagocytosis and by activating the complement cascade. Three co-dominant single base substitutions in codons 52, 54, and 57 of the myoblast city gene result in reduced serum MBL concentrations. Heterozygote advantage may maintain MBL variant alleles at high frequency by conferring resistance to mycobacterial diseases. In a case–control study in Gambia, it was found that the frequency of the common African variant MBL allele (codon 57) was lower among TB cases than controls.
A link between polymorphisms in NRAMP-1 gene and susceptibility to TB has been demonstrated worldwide. Individuals with homozygous type mutation have an increased risk of developing TB. The candidate gene involved with susceptibility to TB in solute carrier family 11 member 1 (SLC11A1) formerly known as NRAMP-1 gene. NRAMP-1 plays a critical role in early innate macrophages responses to intracellular infections., Its pleotropic effects include the activation of microbial responses including the production of reactive oxygen and nitrogen intermediates and proinflammatory cytokines., Initial studies demonstrated an association between four different NRAMP-1 polymorphisms (5'CA, INT4, D543, and 3'UTR) and PTB.
Natural mutant may occur randomly in NRAMP-1 gene but other risk factors such as socioeconomic status, duration of contact, underlying disease, and even other genes can increase susceptibility to TB. The homozygous pattern of NRAMP-1 gene polymorphisms might be associated with susceptibility to TB. This might be one of the reasons why the TB exposed health care workers did not develop TB, even after long periods of working with TB bacillus.
So far, genetic studies of TB susceptibility have largely been focused on adult patients despite the fact that TB is highly prevalent among children. To study the host genetic components of pediatric TB susceptibility using a family-based control design, it was found that allelic variants of the NRAMP-1 gene (alias SLC11A1) is significantly associated with TB disease in the pediatric patient population. Common alleles of the NRAMP-1 gene polymorphisms are risk factors for pediatric TB disease. NRAMP-1 influences the speed of progression from infection to TB disease.
There is evidence for host-environment-agent interaction from infection to disease in TB. Several studies support evidence to state that there is a major role for the host genetics interplay in TB. Based on this, a hypothesis is formulated that is entitled “TB is an infectious disease caused by M. tuberculosis primed and determined by genetic polymorphism.”
Many lines of evidence support an important role of host genetic variation in TB susceptibility including animal models of the disease.,,,,
Polymorphisms in the NRAMP-I gene have been found in a number of genetic studies to be risk factors for the development of TB among adult populations. NRAMP-1 alleles have their highest impact on risk of TB diseases under conditions of low transmission/exposure of M. tuberculosis.
The human NRAMP-1 gene has been implicated in increased risk of TB disease by a number of studies. Polymorphisms in the 5' and 3'regions of NRAMP-1 gene have been linked or associated with TB disease susceptibility in Guinea-Conakry.,, Gambia,,,,,, and South Africa but not in Taiwan or Morocco.
All patients with clinical TB could be classified as fast progressors or primary TB disease cases. Segregation analysis has revealed that the common NRAMP-1 alleles were preferentially transmitted to TB patients. Considering that only 10% of the individuals infected with M. tuberculosis advance to clinical forms of TB, the involvement of genes controlling the rate of progression rather than bonafide susceptibility to TB may offer an effective genetic control of disease risk. Gene-environment interactions are critical for the appropriate selection of efficient host responses and hence, genetic control mechanism. The NRAMP-1 effects are most pronounced in the absence of prior exposure to mycobacteria and NRAMP-1 is a modulator of the speed of progression from infection with M. tuberculosis to TB disease.
To identify the genes responsible for the difference in human susceptibility to TB, polymorphisms of three genes were investigated in a study, namely NRAMP-1, MBL, and CD14 that encode the proteins crucial for the functions of macrophages.
MBL insufficiency due to polymorphisms in the MBL-2 gene causes an opsonization defect and predisposes to recurrent infections in children and adults. The ethnicity may determine the association of MBL polymorphism with the resistance/susceptibility to TB.
It is known that MBL binds mycobacteria strongly, and it has thus been suggested that MBL may facilitate the uptake of mycobacterium by phagocytes. Since macrophages are the living environment for mycobacteria, high MBL serum levels could be a relative disadvantage for the host in relation to these bacteria.
The macrophage CD14 plays a pivotal role in innate immunity. It functions as a multifunctional receptor for bacterial cell wall components and enhances TLRs-mediated signaling. Significant increase in CD14 has suggested a role of the CD14 molecule in the host mycobacterium interactions.
However, it is clear that the association of TB with various polymorphisms in SLC 11 A1 is a feature in many divergent population groups. The possibility remains that SLC 11 A1 is not the disease-associated gene but is in linkage disequilibrium (LD) with such a gene.
Some genes may facilitate hematogenous spread of M. tuberculosis that would lead to a greater association with extra-pulmonary TB (EPTB). Association of the common allele of MBL with both PTB and TB meningitis (TBM) was reported that was stronger with TBM presumably because MBL is a serum lectin and, therefore, aided the blood-borne spread of M. tuberculosis resulting in TBM.
A review search of the literature systematically by means of meta-analysis provided a qualitative summary estimate on the association with TB and the examination of some sources of study on heterogeneity. The summary odds ratios for studies with3'UTR, D'543 N, INT 4 and 5'(GT)n loci allele variants in the SLC11A1 gene were compared with their corresponding common alleles. The study concluded that polymorphisms of the four loci have no statistically significant association between the SLC11A1 variants and susceptibility to TB in subjects of European descent while they showed a statistically significant association in Asian subjects (in except the INT variant), African subjects (except the 3'UTR variant), and the population as a whole (except the INT4 variant).
In another meta-analysis study based on systematically reviewed and published studies on SLC11A1, polymorphisms, and TB susceptibility quantitatively summarized associations of the most widely studied polymorphisms for 3'UTR, D'543 N, INT 4, and5'(GT)n, respectively. There was evidence of the association between SLC11A1 polymorphisms and TB susceptibility, supporting the hypothesis that NRAMP-1 (SLC11A1) gene might play on important role in the host defense in the development of TB.
The most widely studied SLC11A1 polymorphisms; 3'UTR, D'543N INT 4 and 5'(GT)n were identified, and their effects were summarized by means of a meta-analysis.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Significant associations with TB susceptibility were observed for all these four foci. A significant association has been observed for all populations (Africans, Asians, and Westerners) with at least one of the four loci.
The updated meta-analysis based on 36 eligible studies until September 2010 did not present an ethnic-specific effect of SLC11A1 polymorphisms. Three ethnic groups were defined with respect to the distribution of the study population in the included studies, e.g. Asians, Africans, and Westerners (Europeans and Americans). Statistically significant or marginal associations with TB susceptibility were found for the four studied loci in all the three ethnic groups. A large number of included articles in the study make the evidence stronger to propose a consistent effect of SLC11A1 polymorphisms in the different populations. Moreover, the effects and role of polymorphisms of NRAMP-1 in the development of TB might not be disease type-specific.
A case–control study on sex- and age-dependent associations of SLC11A1 polymorphisms with TB in Chinese showed the association of the polymorphisms SLC 6a (D'543N) and SLC 6b (3'UTR)of the SLC11A1 locus with TB. It also found a significant association with the 3'polymorphisms of SLC11A1 that was restricted to female patients and young patients.
Currently, the research hot spot is mainly on candidate predisposing genes of non-HLA such as VDR gene NRAMP-1 gene and mannose-binding protein (MBP).
People with low Vitamin D content in serum face, higher risk of suffering from TB. Vitamin D plays its role through VDR so that the polymorphism of genes may affect the activity and the subsequent mediated effect of VDR; it has been considered as a risk factor in a large number of clinical outcomes.
VDR gene has many polymorphic loci and the most extensive research is focused on the Fok I and 3/noncoding regions (Taq I, Apa I, and Bsm I). This locus could be recognized and digested by the Fok I restriction end nuclease and thus, display polymorphism.
Many studies have shown evidence of the association between host genetics polymorphisms and TB susceptibility including CCL-2/MCP-1, NRAMP-1/SLC11A1, IRGM-1, IL-8, TLR, and NOD-2 genes.,,,,,, Most of these genes participate in immune response and their polymorphisms may lead to increased genetic susceptibility to TB.
The genes for low molecular weight polypeptides (LMPs) and transporter with antigen processing (TAP) are located within the major histocompatibility complex (MHC) Class II region of chromosome 6 between the HLA-DP and HLA-DQ loci and have been shown to play a critical role in the processing and presentation pathway for intracellular antigens.
These data establish that MHC Class I antigen processing pathway that requires cleavage of antigen peptides by LMP2/LMP7 and transportation of peptide fragments into the endoplasmic reticulum by TAP 1/TAP 2 is vital for controlling M. tuberculosis infection and preventing the development of active TB.
A few of the polymorphisms (TAP 1 and TAP 2) have been studied to determine the predisposition toward TB in different ethnic groups that have revealed susceptibility to TB.,
LMP and TAP polymorphisms may differ among populations as reported by many studies. Significant association between LMP/TAP genes and TB was observed in a study where active TB patients and controls were compared. The subjects containing LMP 7AA homozygote and CA heterozygote were found to be strongly associated with TB infection. Similarly, the TAP 1–2 polymorphisms also exhibited a significant relation to TB infection. Similar to the individual single-nucleotide polymorphism (SNPs), it was observed that haplotype B that carried LMP 7 and TAP 1–2 variations significantly increased the susceptibility to TB.
The critical roles of the LMP/TAP genes are consistent with the observed association for TB. In a study, it was first reported a statistical association between alleles in TAP 2 region with PTB and tuberculoid leprosy susceptibility in the North Indian population.
There is supporting evidence for the association between LMP gene polymorphisms and human susceptibility to TB disease. Evidence also supports the hypothesis that MHC Class I-mediated antigen presentation may play an important role in the host defense to TB.
The majority of the population infected with M. tuberculosis maintains a latent state and do not convert to clinical disease, but do remain at risk of progressing to active TB later. Factors that can modulate progression to active TB include gender, anemia, smoking and alcohol consumptions as well as bacterial and host genetic factors.,, Evidence from human and animal studies indicate that M. tuberculosis clearance in genetically regulated. Twin studies, genome-wide linkage, and association analysis as well as candidate gene studies support the notions that human genetic factors play a role in the development of TB. The majority of the genes that have been implicated so far are in immunological pathways.
CCL-2/MCP-1 encodes the CCL-2/MCP-1 protein, a member of the CC cytokine subfamily that is characterized by two cysteine residue motif proximal to the amino terminus of the protein. The MCP-1 chemokine plays a key role in the granulomatous reaction in lung tissue and M. tuberculosis containment in mouse models occurs through interaction with the cognate receptor, chemokine (C-C motif) receptor-2 (CCR-2). The chemokine MCP-1 was associated with severe TB and was proposed as a marker of disease severity.
The 17q11–q21 chromosomal region encompassing MCP 1 was initially identified as a candidate for TB susceptibility in linkage analysis of multicase-TB and leprosy families from Brazil and the critical interval was subsequently refined to 17q11–12.
To comprehensively evaluate the genetic risk of polymorphisms (D'543N, 3'UTR, TG ins/del, INT 4, [GT] n) in the SLC11A1 gene for TB, a total of 82 case–control studies in 35 articles were included. The results showed that these four polymorphisms were associated with an increased risk of TB. The meta-analysis suggests that polymorphisms in the SLC11A1 gene contribute to TB (both PTB and EPTB), particularly in Asians.
The VDR gene has been studied in several studies as a candidate locus due to genetic polymorphisms that affect the activity of the receptor and subsequent downstream Vitamin D-mediated effects. Among Asians, the Fok l FF genotype showed a pronounced positive association, a significant inverse association was observed for the Bsm1 Bb genotype and marginal significant associations were found for Taq 1 and Apa 1 polymorphisms. However, none of the polymorphisms was significantly related to TB among Africans or South Americans. The association of VDR polymorphisms with risk of TB observed support of the hypothesis that Vitamin D deficiency might play a role as a risk factor during development of TB.
The VDR is involved in a wide range of biological functions, including meditation of Vitamin D3, interactions with the immune system.,,,, Among UK Gujarati Asians, the FF genotype was associated with an increase in TB susceptibility, particularly EPTB.
In South Indians, the Taq1 and Fok 1 variants as well as two others, Bsm 1 and Apa 1 restriction fragment polymorphisms both in intron 8, were examined in a case–control study involving patients with spinal TB. The Bsml Bb genotype was found to be elevated in patients, as was the FF. In a comparison study, the FF genotype was associated with active PTB among males while in females, the TT genotype was associated with spinal TB., Although VDR data appear to be in conflict across populations, this may be explained by the multiple roles of Vitamin D3 suggesting that higher utilization of Vitamin D3 for those with the FF genotype may result in lowered serum Vitamin D3, increasing risk for spinal TB.
As a member of the epidermal growth factor (EGF) family, epiregulin (EREG) is better known for its role in cell growth and homeostasis. Evidence supports a broader biological role for EREG with evidence that it is involved in the macrophage response to M. tuberculosis infection.
The polymorphism associated with TB is located within an intronic region of the EREG gene and is likely a genetic marker in LD with the functional and disease causative allele.
There is evidence to support the hypothesis that some strains of M. tuberculosis are more virulent than others. This suggests that the causative variant of EREG may be associated with an impaired immune response to M. tuberculosis leading to more aggressive disease, prolonged bacteremia, and an increased chance of seeding to the meninges. This demonstrates a further significant interaction between host and bacterial genotypes and the development of TB. This provides the first evidence to suggest an important role for EREG in the human immune response to TB.
One of the first reports of an association between HLA and TB showed an increased frequency of HLA-B8 in Canada. Other studies showed an increased frequency of HLA-B5, B15, and DR 5 in the North American Black population, HLA-A2, and B5 in the Egyptian population and B27 in the Greek population.
A significantly increased frequency of HLA-DR2 was seen in the major studies those have revealed HLA-DR2 association with higher susceptibility to TB in Russia, China, and Canada. An increased frequency of HLA-DR2 and HLA-DQ1 was shown to be associated with the susceptibility to PTB in the Indian population. Molecular study has revealed that the allele DRB*1501 of HLA-DR2 was higher compared with DRB*1502 in North Indian patients. HLA-DRB1*1501, HLA-DQB1*0601 (a subtype of HLA-DQ1) and DPB1*02 were found to be positively associated with susceptibility to PTB in Indian patients.
TB and HIV coinfections place an immense burden on healthcare systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful risk factor predisposing to M. tuberculosis infection and progression to active disease that increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of acquired immune deficiency syndrome (AIDS)-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death of untreated patients. TB is the largest single cause of death in the settings of AIDS. Various lines of evidence indicate that inborn errors of immunity as well as genetic polymorphisms have an impact on the susceptibility to TB and HIV.
Cell-mediated immunity is essential for the control of M. tuberculosis infection; activation of both CD4 and CD 8 T-cells seen in active TB in humans, as well as in mice after experimental infection. T-cells recruited to the infected lung are thought to control infection by producing IFN-gamma in response to mycobacterial antigens presented by macrophages.[91.92] In turn, IFN-gamma activates macrophages to kill the intracellular bacteria through reactive nitrogen and oxygen intermediates and by inducing phagosome formation.
Maxine Caws et al. in a study, on the influence of the host and bacterial genotype on the development of the disseminated disease with M. tuberculosis, provides evidence that M. tuberculosis genotype influences clinical disease phenotype and demonstrates a significant interaction between the host and bacterial genotypes and the development of TB.
Defining the contribution of host genetic polymorphisms to disease susceptibility based on studies has suggested that polymorphisms in several genes are associated with the development of PTB. Some of these genes with polymorphism that have been validated in multiple studies and may have an effect on gene functions including solute carrier family 11 member 1, SLC11A1, formerly NRAMP-1,,,,, IFN-gamma,, TIRAP/MAL, P2XA7, (Fernando et al., 2005), and CCL 2 or MCP-1.,,
Studies provide evidence that M. tuberculosis genotype influences diseases phenotype. Also, there is evidence to support the association between the host and bacterial genotype in concert in M. tuberculosis disease.
Here arise certain important research questions:
- Why do not all M. tuberculosis-infected persons develop TB disease?
- Why do not all immune compromised and infected patients progress to TB disease?
- Even though the risk of developing TB in high among HIV-infected people, why do not all HIV-infected and AIDS patients develop TB?
- Why do not all patients with diabetes mellitus who are infected with M. tuberculosis develop TB?
- Why do not all family members and contacts of the patients with PTB develop TB disease?
- Why all health care providers attending to patients with PTB are not developing TB diseases?
- Why is there a difference in prevalence of the disease in different geographical areas and ethnic group?
If we go through the relevant scientific data for the answers, they will guide us to the genetic factors of both the host and the pathogen.
After perusing several well-documented research works, various salient observations and conclusions, there is sufficient evidence to prove that TB is a genetically primed and determined infectious disease caused by M. tuberculosis and the genetic polymorphism is the mechanism that leads to progression from infection to TB disease.
The proposed hypothesis and algorithms of “Genetic Polymorphism and TB” is given in [Figure 1].
According to this theory, TB is an infectious disease caused by M. tuberculosis, primed and determined by genetic polymorphism. The M. tuberculosis is not the only determining factor toward progression. Genetic factors play a major role in the pathogenesis. In addition, genetic factors influence the immune responses of an individual. Polymorphisms in the different genes can influence and modulate the immune responses and that is why all M. tuberculosis infected people are not progressing to TB disease.
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