Understanding Epigenetics Tuberculosis And TB HIV Coinfection Biology Essay

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The completion of the Human Genome Project is without a doubt one of mankind's greatest achievements. We now have an almost complete list of genes that are required to produce a human. The situation is however more complex than a list of genes. There is a system of equal importance, one which determines when and where a particular gene will be expressed during development. This system is embedded in DNA in the form of epigenetic marks. These epigenetic marks are usually inherited during cell division but bring about no changes to the DNA sequence. The goal of the Human Epigenome Project is to identify all chemical changes and relationships among chromatin constituents that provide function to the DNA code. These findings will enhance our understanding of aging, abnormal gene control in cancer and other diseases as well as the role that the environment has on human health. Epigenetic studies have taken the forefront in cancer research and it has been proven that cancer cells have aberrant methylation patterns, this information has since been applied in therapy and treatment programmes. Tuberculosis (TB) is the second leading cause of death worldwide. It claims the lives of nearly 2 million people each year. The incidence of tuberculosis has increased in Africa in the past decade; this is mainly due to HIV infection. This paper reviews epigenetics and its marks as well as Tuberculosis and TB/HIV coinfection in an attempt to provide understanding of these concepts.

Epigenetics

The term epigenetics was first used by Conrad Waddington in 1939. It described the interactions between genes and their products, which bring the phenotype into being (Waddington 299-307)Subsequently Arthur Riggs and colleagues defined epigenetics as the "study of mitotically or meiotically heritable changes in the gene function that cannot be explained by changes in DNA sequence" (Bird 396-98). The Greek prefix "epi" in epigenetics implies features that are "on top of or in addition to" genetics, thus epigenetic traits occur on top of or in addition to the normal molecular basis of inheritance. Since there are no changes that take place in the DNA sequence, non-genetic factors cause the organisms' genes to behave or to express themselves differently (Baker 181-86).The two predominant epigenetic mechanisms are DNA methylation and histone modification. Activation of certain genes is influenced by epigenetics. Epigenetic changes are preserved when cells divide and the changes only occur within the course of one individual organism's lifetime. However if a mutation were to take place in the DNA some epigenetic changes are inherited from one generation to the next. Epigenetic processes include paramutation, imprinting, gene silencing, X chromosome inactivation and the progress of carcinogenesis (Li 662-73).

To further our understanding of the epigenetics phenomena and how they are implicated in diseases a large number of molecular biologic techniques are used. These include chromatin immunoprecipitation, fluorescent in situ hybridization, methylation-sensitive restriction enzymes, and DNA adenine methyltransferase identification (DamID) as well as bisulphite sequencing (Trygve O.Tollefsbol 1-8). The use of bioinformatics plays an important role in computational epigenetics. Bioinformatics programs such as BiQ Analyzer provide support for the visualisation of DNA methylation data once bisulfite sequencing has taken place (Bock C 4067-68).It is important to know and understand the genome-wide distribution of DNA methylation in healthy cells and how a whole genome should epigenetically look like in a healthy cell, this information is provided by bioinformatics programs such as the web-based data mining tool (Bock, Lengauer 2006). The phenotype expressed by an individual depends on the genes that are transcribed. Thus genes are regulated in a number of ways of which DNA methylation is one. Epigenetic states can be divided into three categories: euchromatin, constitutive heterochromatin and facultative heterochromatin (Arney and Fisher 4355-63).These subgroups depend on the type of modification that occurs.

Modifications such as acetylation of histone 3 and histone 4 are referred to as euchromatin modifications. Heterochromatin modifications are those that are localised to inactive genes or regions (Li, Carey, and Workman 707-19). However most modifications take place in the upstream region, the core promoter and the 5' end of the open reading frame (Li, Carey, and Workman 707-19). The inactive X chromosome is made of facultative heterochromatin. Facultative heterochromatin modifications are characterised by histone H3 which is dimethylated at lysine 9 and trimethylated at lysine 27 (Chadwick and Willard 17450-55).These modifications are acquired early during random X inactivation and it is achieved by histone methyltransferase enzymes (HMTase) (Chadwick and Willard 17450-55).

Figure . Examples of Epigenetic marks obtained from Katie Vkarl

Histone modifications

Histone proteins make up the nucleosome around which DNA is tightly packaged. The N-termini of histone polypeptides are modified by a large number of different posttranslational modifications which include acetylation, methylation, phosphorylation and ubiquitination (Kouzarides 693-705). Acetylation is the addition of an acetyl (CH3CO) group usually to the lysine residues located on the N-terminal tails of histones. It relaxes the binding between histones and DNA, hence promoting transcription in eukaryotic cells. The acetylation status (gain or loss of an acetyl group) of histones is determined by two proteins namely histone acetyltransferase (HATs) and histone deacetylases (HDACs) (Gibbons R85-R92). HDACs are known to remove acetyl groups and thus give rise to gene repression (Gibbons R85-R92). Ubiquitination is a process by which ubiquitin protein ligases add a polyubiquitin chain to target proteins that are to be destroyed through hydrolysis. Phosphorylation involves the addition of a phosphate (PO4) group to a protein or molecule (Klug W). It is known to activate or deactivate many protein enzymes and thus t is associated with causing or preventing the disease mechanisms of cancer and diabetes. ADP-ribosylation is a post-translational modification of mediated proteins which is carried out by ADP- ribose polymerases that use NAD+ as a substrate (Quqnet et al. 60-65).

DNA Methylation

DNA_Methylation

Figure A. methyl group is added by methyltransferases to the CpG Site. B. Differences between methylated and unmethylated DNA. C. Differences between 'Normal" DNA and Cancer DNA .Cancer DNA appears to be hypermethylated compared to the 'normal' DNA. The figure was obtained from http://www.cellscience.com/reviews7/Taylor1.jpg

This is the most well-characterised epigenetic modification with its information content related to local density within a genomic region. For this reason the current review will concentrate on DNA methylation. It has been suggested that DNA methylation affects genes that are already silent and does not interfere with active promoters. An example is observed in X chromosome inactivation in the mammalian embryo (Bird 396-98). A minor disruption in methylation density can be lethal during development, and a large number of developmental abnormalities and diseases have been associated with abnormal methylation patterns (Robertson 597-610); (Schaefer et al. 398-99).In some mice studies it was shown that a deletion to anyone of the known active DNA methyltransferases leads to embryonic lethality (Rohde et al. e34) The majority of these modifications are not well understood, however research in progress has increased our understanding of the roles that methylation and acetylation play in transcriptional regulation (Barski et al. 823-37).

During the process of methylation in DNA, methyl groups are added usually at the CpG sites. CpG sites are regions on DNA in which cytosine occurs next to guanine in a linear fashion along its length. The cytosine and guanine are separated by a phosphate which acts as a linkage for these two nucleosides (). In such a process cytosine is converted into 5-methylcytosine (Robertson 597-610).Approximately 1% of bases in a somatic human genome are methyl-cytosines, which is equal to 70%-80% of all CpG dinucleotides in the genome (Hirst and Marra 136-46). The behaviour of the cytosine however does not change as it continues to bind with G even when methylated. The extent to which areas of the genome are methylated determines the transcriptional ability of those areas as we would expect highly methylated areas to be transcriptionally less active. However we need to take note that not all CpG sites are methylated as DNA methylation is tissue specific (Robertson 597-610).The known biochemistry of DNA methylation allows us to explain somatic inheritance of epigenetic states (see below). DNA methylation is stable for years in frozen or prepared tissue samples and when purified, DNA is easily assessed with various methods. DNA methylation is thus the information layer of choice when studying the epigenome.

Inheritance of DNA methylation patterns

The manner in which DNA methylation patterns could be inherited through generations of somatic cells was first suggested by Riggs, Holliday and Pugh in two seminal papers which were published about 32 years ago. They hypothesised that DNA methylation can change the expression of genes by influencing the binding affinities of transcription factors or other proteins to DNA; that there are varying patterns of DNA methylation; and that these patterns differ in different cell types .The key to somatic inheritance was proposed to be the existence of enzymes that catalyse the methylation of hemimethylated DNA that is generated during DNA replication (Holliday and Pugh 226-32).Simply put, when a methylated CpG dinucleotide is replicated, the C on the strand that is starting to develop is not methylated at first and the proposed enzymes will replicate the parental pattern of methylation (Holliday and Pugh 226-32).This prediction led to the idea of the presence of maintenance DNA methyltransferases' (maintenance DNMTs) that could ensure somatic inheritance by copying patterns that were established in the early embryo by de novo DNMTs or so-called 'switch enzymes' (Jones and Liang 805-11).

DNA methylation in prokaryotes differs from that of eukaryotes as prokaryotes only have one DNMT per strain whereas eukaryotes have maintenance and de novo DNMTs (Jones and Liang 805-11).Prokaryotes can maintain DNA methylation due to the fact that they have equally effective DNMTs on both methylated and hemimethylated DNA. Thus the major difference in the maintenance patterns of prokaryotes and eukaryotes was suggested to be a DNMT preference for hemimethylated DNA which is found in prokaryotes (Margot, Ehrenhofer-Murray, and Leonhardt 7).

Studies performed with mouse embryonic stem cells have shown results that do not fit the proposed model. These stem cells have a single DNMT1 and show no methylation of imprinted genes and repeats, and thus methylation of other sequences are lost as the number of divisions increases (Chen et al. 5594-605).Studies which were performed by the bisulfite method have suggested that methylation patterns show molecule to molecule variation (Riggs and Xiong 4-5).

The fact that some experimental observations did not fit the original proposed model led to further studies being undertaken. Two de novo DNMTs, DNMT3A and DNMT3B, were cloned by Okano et al. and were said to be responsible for establishing the pattern of methylation in embryonic development. A similarity between these enzymes and prokaryotic DNMTs is that they show equal activities on hemi and unmethylated DNA. DNMT3A and DNMT3B are necessary for embryonic viability of mice and mutations in them may lead to human diseases such as Immuno-deficiency centromere instability and Facial abnormalities syndrome (Xu et al. 187-91). DNMT1 was cloned by Bestor et al and shown to have a preference for hemimethylated DNA (Hermann, Gowher, and Jeltsch 2571-87). This enzyme is transcribed mostly during the S phase of the cell cycle, it is needed to methylate newly generated hemimethylated sites (Robertson et al. 338-42).However, knockout experiments have shown that most of the methylation in mouse cells is due to this enzyme (Li, Bestor, and Jaenisch 915-26). A recent review by Cedar et al emphasised that a division exists in the functions of de novo enzymes and DNMT1. It is said that de novo enzymes establish methylation patterns and DNMT1 is responsible for copying those methylation patterns .Thus the two non-over(Jones and Liang 805-11)lapping functions of these enzymes determine DNA methylation patterns.

Maintenance methylation

How epigenetic information is passed through generations

The processes that produce DNA methylation patterns between cell generations are described as maintenance methylation. This mechanism of reproducing methylation patterns depends on semiconservative copying whereby the parental strand of the methylation pattern is copied onto the progeny DNA strand (Holliday and Pugh 226-32). DNMT1 has a high preference for methylating the new CpGs when their partners on the parental strand already carry a methyl group (Bestor 2611-17). In this way both the methylated and nonmethylated CpGs are copied along a strand of DNA and this provides a way of passing epigenetic information between cell generations (Bird 6-21). CpG islands appear to keep their methylation states stable, whether methylated or not, across many cell generations (Bird 6-21).

Methylation fidelity

The term fidelity refers to the degree of accuracy with which something is copied or reproduced. In this case it is the degree to which CpG sites are methylated. A CpG site can either be methylated or unmethylated thus methylation levels are expected to be 0% or 100% at times for a given allele (Jones and Liang 805-11). Methylation levels for specific CpG sites measure the average of all DNA molecules in a tissue and thus will be difficult to quantify. Stable inheritance of average methylation levels is however found in specific sites in mouse tissues and cell lines (Pfeifer et al. 8252-56).Riggs and Xiong thus suggested that the average state is maintained by a stochastic process that requires ongoing de novo methylation. The data exclude the possibility that the heterogeneity is caused by the faithful copying of a series of heterogeneous patterns that were set up in development (Jones and Liang 805-11).

Methylation detection methods

The ability to identify methylation in the promoter regions of particular genes has proven to be a useful tool in the molecular diagnosis of human diseases (Kholod, Boniver, and Delvenne 574-81). In bacterial genomic DNA the identification of these methylated sites can be used to study the role of DNA methylation in prokaryotes. This role has been proposed to be repairing post-replicative mismatch, controlling DNA replication, distinction of self and nonself DNA, as well as controlling the level of gene expression (Bart et al. e124). The epigenetic information which is available in methylated DNA has been proved to become lost during subcloning or PCR, therefore it is essential to choose the right technique (Rohde et al. e34).

Southern blot and the use of restriction enzymes combined with PCR were among the first methods used to analyse methylation patterns (Sulewska et al. 315-24). The use of this method enables overall assessment of the methylation status of CpG islands. However large amounts of DNA are required to carry out this experiment and another limitation is that only the CpG sites that contain the recognizable cutting area of the applied restriction enzyme will produce information (Sulewska et al. 315-24).

In 1989 a PCR method that used primers which flanked the sites digested with the restriction enzyme HpaII was designed. This method was based on the treatment of DNA with HpaII, before PCR was applied. The templates which are methylated will be protected from enzyme cutting, thus all unmethylated DNA had to be cut (Singer-Sam et al. 4987-89). However, as with Southern blot, only sites with methylation-sensitive restriction sites will give the CpG methylation status. This method is useful in the analysis of imprinting, as well as X chromosome inactivation. Another limitation that arose with this method was the inability to differentiate between completely cut unmethylated DNA from a low quantity of methylated alleles (Sulewska et al. 315-24). Thus it cannot be used in the detection of hypermethylation or when there is a small amount of DNA within methylated alleles (Singer-Sam et al. 4987-89).

The bisulfite method is based on the bisulfite conversion of unmethylated cytosines in single stranded DNA (Sulewska et al. 315-24). When DNA is bisulfite treated a chemical conversion from unmethylated cytosine to uracil occurs (as in step 1 in Figure 1). However, 5-methylcytosine remains nonreactive (Frommer et al. 1827-31). Regions of interest in the bisulfite converted DNA template are amplified using PCR with two sets of strand-specific primers to give a pair of fragments, each one originating from each strand.

Bisulfite method

Figure . Bisulfite conversion of sample sequence to genomic DNA. Step 1. Unmethylated cytosines are converted to uracil by sodium bisulfite. Figure obtained from Vallian and Nassiri 2009

The interesting aspect of this method is that both uracil and thymine residues are amplified as thymine and the methylated 5-methylcytosine residues remain amplified as cytosine (Frommer et al. 1827-31). The accurate position of the 5-methylcytosine is given by a positive band on a sequencing gel (Frommer et al. 1827-31). The PCR products can then be sequenced to give methylation maps or single DNA molecule directly. Once the PCR reaction is completed the rate of methylation at the CpG is determined. This is achieved by assessing the proportion of the remaining cytosine relative to the thymine.

Epigenetics and human diseases

Histone modifications as well as DNA methylation play a very important role in the proper functioning of the cell and also in cellular identity (Veeck and Esteller 5-17). In the past decade it has become clear that epigenetic malfunction may play a role similar to that of genetics in the development of cancer (Holliday 163-70). For example it has been shown that the enzymes (Dnmt1, Dnmt3a, and Dnmt3b) which have been identified as being responsible for maintaining as well as establishing methylation patterns are found to be expressed excessively in cancer, which may suggest that they favour the development of the malignant phenotype (Veeck and Esteller 5-17) . The retinoblastoma tumor suppressor (RBI) gene which is hypermethylated has brought about confirmation in the role that DNA methylation plays in tumorigenesis (Greger et al., 1989).

Recently microRNAs (miRNAs) have received a lot of attention in oncology research.These RNAs result in the inhibition of mRNA translation (He and Hannon 522-31). A well known member of the miRNA family is let-Z the decrease of which in breast, lung and colon cancer has correlated with an increase in tumorigenicity (Yu et al ., 2007).In normal cells miRNA are highly regulated to ensure a distinct transcriptome, however it has been found that in breast cancer they are down regulated (Iorio et al. 7065-70). The degree of this down regulation can thus be used to determine how aggressive the cancer can be (Foekens et al. 13021-26).

The patterns in which DNA is methylated differ between normal cells and cancer cells. DNA hypomethylation which is a decrease in 5-methylcytosine content in the DNA has been shown to aid the activation of cells that could potentially be oncogenes (Wilson, Power, and Molloy 138-62). Immuno-deficiency Centromere instability and Facial abnormalities (ICF) is characterised by global hypomethylation which is a result of a mutation in the DNMT3B gene. In this syndrome the DNA repeat sequences at the centromere and genomic instability in tissues is affected by the degree of hypomethylation (Tuck-Muller et al. 121-28). Hypomethylation in breast cancer has shown to affect repetitive DNA sequences that are known to be heavily methylated in non-malignant cells (Bernardino et al. 83-89).In ovarian and breast cancer the Sat2 and Satα repeats appear to be hypomethylated (Widschwendter et al. 4472-80). Hypermethylation has been proposed to have an effect on cancer development; however the exact mechanisms are still not clear (Veeck and Esteller 5-17).It is apparent that cancer cells may have a complex pattern which is contributed to by the interconnection of genetic and epigenetic lesions.

A link between disease and environmental influences has been demonstrated during early development. An example is the link between low birth weight and an increased risk of hypertension, stroke, and type 2 diabetes osteoporosis (Godfrey and Barker 1344S-1352). This usually occurs when an individual organism tries to adapt to the environment surrounding it by epigenetic changes which are heritable (Wan-yee Tang and Shuk-mei Ho 173-82) and it is known as developmental reprogramming or imprinting. However these epigenetic changes may predispose the individual to diseases once the environmental conditions previously adapted to, change (Gluckman and Hanson S47-S50). The embryo goes through a range of demethylation which results in a loss of CpG methylation (Reik, Dean, and Walter 1089-93). In order for these methylation patterns to be restored nutritionally supplied methyl donors such as methionine and folic acid must be supplied (Waterland and Jirtle 5293-300).When there is not enough folate during development, diseases such as coronary artery disease arise with a reduction in genome methylation (Castro et al. 1292-96).

Prada-Willi syndrome (PWS) and Angelman syndrome (AS), which are characterised by mental retardation and behavioural abnormalities, are believed to be a result of defects in genes that encode components of the DNA methylation pathway. These diseases arise from changes or aberrations to the imprinting control region at 15q 11-q13 (Goldstone 12-20).The pathology of this diseases is brought forward by either deletion or de novo methylation of the parental allele, in the case of PWS or maternal allele in the case of AS (Runte et al. 2687-700).Fragile X syndrome (FRAXA) is an X-linked disorder in which the expanded polymorphic CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR 1) gene is hypermethylated which leads to the silencing of FMR 1 transcription (Oberle et al. 1097-102).

DNA methylation is not the only epigenetic trait associated with human diseases; recent studies have shown that there is a link between histone methylation and neurological disease (Shi, 2007). One such example is the neurological disorder known as Sotos syndrome which is described by cerebral gigantism and mild mental retardation (Faravelli 24-31) .

Epigenetics has become a recent focus in the explanations of age related autoimmune diseases (Hirst and Marra 136-46). Autoimmunity occurs when an individual fails to recognise self, causing an immune responses to be raised against its own cells and tissues, mostly through the actions of T and B white blood cells (Hirst and Marra 136-46). Rheumatic disease is an example of an association between DNA methylation and autoimmunity (Rahman and Isenberg 2008). Recently findings have also shown that histone modification may play a role in the development of rheumatoid arthritis.

Figure 2 shows that the field of epigenetics and disease has experienced exponential growth in the past years (Hirst and Marra 136-46).However, limitations arise as there is a lack of understanding of how most of the epigenetic marks work in the eukaryotic genome. The studies of epigenetics are thus conducted with the hope that knowledge will be gained and then applied in the designing of therapeutics. In cancer therapy for instance, DNA demethylating drugs are supplied to patients in low doses and have been shown to act against some tumours (Esteller 1148-59).

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Figure . The number of papers available in pubmed per year using the keywords Epigenetics and Disease.

Tuberculosis

Tuberculosis (TB) is a major health, social and economic burden in most developing countries. It is an infectious disease that is responsible for the death of almost 2 million people each year (World Health Organisation). Although it is primarily known to be a pulmonary disease it also affects the bone, the central nervous system as well as other organ systems (Smith 463-96).

The disease is primarily caused by inhalation of airborne droplets containing Mycobacterium tuberculosis (Mtb) in humans (Lykouras et al. 24-31). The M. tuberculosis germs cause holes in the lungs which can cause difficulty breathing and coughing up blood. The symptoms associated with this disease include a cough that lasts longer than two weeks, fever, night sweats, weight loss, chest pain and haemoptysis (Miller et al. 293-99). Fortunately, not everyone who comes into contact with TB becomes sick. The body has the ability to form a fibrosis around the TB bacteria which helps in keeping the infection in an inactive state. Only about 10% of people who are infected will develop the active form of the disease at some point (Möller, de Wit, and Hoal 3-26).

Progression of the disease is largely determined by the ability of the host immune system to respond. Moreover, the efficiency of this response can be affected by both internal and external factors. Internal factors are composed of the genetic makeup of the immune system and the external factors include nutrition, environment, and the immunocompetency of the host (Smith 463-96). Studies have shown that genetic factors play a role in the outcome of tuberculosis; the heritability ranges from 36% to 80% (Kimman, Janssen, and Hoebee 483-92).

Post inhalation of M. tuberculosis the body can react in three possible ways: the infection can develop into active tuberculosis, it can be killed by the pulmonary immune system, or the bacteria can be contained in granulomas and not develop into active disease (Kaufmann and McMichael 578) .

In an effective host immune system the alveolar macrophages which are infected with TB interact with T lymphocytes via several important cytokines (Frieden et al. 887-99). When the macrophage becomes infected it releases interleukins 12 and 18 which then leads to the stimulation of CD4 positive T lymphocytes (Frieden et al. 887-99). Interferon γ is then released and stimulates the phagocytosis of M. tuberculosis. However, it does not lead to the direct killing of the bacteria because its transcriptional responses are inhibited by the bacteria. Interferon γ is essential for infection control and the releasing of necrosis factor α which is essential for granuloma formation (Frieden et al. 887-99). A number of genes and their polymorphisms are associated with tuberculosis. For example, the natural resistance-associated macrophage protein 1 (NRAMP1) targets the phagosome once the bacterium has been phogocytosed to change the environment in such a way that the replication of the bacterium is influenced (van Helden et al. 17-31).

Tuberculosis and HIV Co-infection

Approximately 40 million people are living with HIV around the world and a third of these are co-infected with tuberculosis (TB) (World Health Organisation) . In Sub-Saharan Africa alone about 80% of patients observed at state hospitals and clinics have been shown to be TB/HIV co-infected. Due to lack of appropriate treatment 90% of people living with HIV die within a few months of contracting TB (World Health Organisation). This significant number of deaths is one of the reasons why TB/HIV co-infection is commonly referred to as the "deadly duo".

TB and HIV have a synergistic interaction where one accelerates the progression of the other (Sharma, Mohan, and Kadhiravan 550-67). People with HIV/Aids have a 50% greater chance of developing active TB than HIV negative people. The growing mortality rate among people with HIV is mostly due to the increase in the number of TB infections. HIV weakens the immune system, thus people who are infected are more susceptible to contracting TB when the opportunity of exposure arises (Corbett et al. 1009-21).

In communities where the prevalence of HIV is high (above 30 percent amongst pregnant women), annual TB rates as high as 1 500/100 000 were reported in 2004. However, an increase has been noted since then (World Health Organisation). The biggest problem that arises with TB/HIV co-infection is at diagnosis. This is due to the fact that in HIV patients, TB is likely to occur inside and outside the lungs (Yamada and Nagai 203-11).

Treatment of TB/HIV could be a difficult task as there could be interaction between the drugs regimens required to treat both diseases. People with HIV/Aids often develop Immune Reconstitution Inflammatory Syndrome (IRIS) which is an overreaction of the immune system that exacerbates TB (French, Price, and Stone). There is an urgent need to find ways to manage IRIS and possibly reduce the time in which TB treatment should be administered. This is of vital importance as it could prolong the lives of people living with HIV by at least two years and possibly longer if Aids medication is given quickly. Patients with HIV/Aids have a higher risk of developing drug resistant TB because the absorption of medication might be compromised due to the disease.

Host genes and tuberculosis susceptibility

Susceptibility to tuberculosis (TB) is influenced by many factors. Host genetic factors play an important role in the susceptibility or resistance to TB (Hill 593-617). These are the factors that give an explanation as to why some people develop a TB infection and others do not. The previous health status and acquired immunity of a person as well as the variability in the pathogen make it hard to determine the ways in which a person will respond to infectious agents.

The expectation that disease is genetically determined led to numerous twin studies that have been used in order to support that host genetics plays a role in susceptibility to TB. In these studies the disease status among identical and non-identical twins where compared (Comstock 621-24). It was found that there was a high concordance for tuberculosis among monozygotic twins (who are identical in their genetic makeup) compared to dizygotic twins (who are not identical) (Comstock 621-24). This further contributes to the original statement that genetic factors play a role in susceptibility to TB as the twins in the studies shared the same environment.

Human leucocyte antigen (HLA) and non-HLA genes are host genetic factors which have been studied to illustrate the link they have with susceptibility or resistance to TB. The findings will aid in providing HLA genetic markers that could assist in predicting the development of TB (Selvaraj P). Understanding the role of these markers will be useful in understanding the immunopathogenesis of the disease and will aid in the management and control of the disease.

The link between genetic polymorphisms and tuberculosis susceptibility differs according to ethnic origin (Frieden et al. 887-99). HLA association studies have been done in non-Asian countries and in a study where HLA and TB association was done in Canada there was an increase in HLA -B8 (Selby et al. 403-08). HLA-DR2 has been shown to be associated with higher susceptibility to TB.

However, HLA are not the only factors associated with TB susceptibility. In north India, susceptibility to pulmonary TB was associated with HLA-DR2 as well as the 'Transporter' associated with antigen processing gene 2 (TAP2). However, geographic variation and racial differences play a role in susceptibility. This phenomenon is explained by the association between TB and the haptoglobin 2-2 phenotype in Russian patients which was not found in Indonesians and Indians (Selby et al. 403-08).

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