TB

REVIEW doi: 10.1111/j.1365-3083.2012.02696.x ..................................................................................................................................................................
DNA Sequence Variation and Regulation of Genes Involved in Pathogenesis of Pulmonary Tuberculosis
T. Qidwai*, F. Jamal* & M. Y. Khan
Abstract
*Department of Biochemistry, Dr. R.M.L. Avadh University, Faizabad, U.P., India; and Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, U.P., India
Received 9 October 2011; Accepted in revised form 23 February 2012 Correspondence to: Dr F. Jamal, Department of Biochemistry (DST-FIST & UGC-SAP Supported), Dr. Ram Manohar Lohia Avadh University, Faizabad224001, U.P., India. E-mails: farrukhrmlau@ gmail.com; journal.farrukh@gmail.com
DNA sequence variations [copy number variations, single nucleotide polymorphisms (SNPs) and microsatellite repeats] play an important role in susceptibility resistance to tuberculosis and other infectious diseases like malaria and HIV. Different population exhibit variable associations with tuberculosis susceptibility and severity because of DNA sequence variations in both host and parasite. A number of genes and their polymorphisms have been identied that appear to be important in tuberculosis. In this article, several casecontrol studies of tuberculosis including a number of genes in different population have been explored. Furthermore, this review summarizes the current studies of host polymorphisms and their association with tuberculosis in different population. We have computationally predicted 275 SNPs which occur in transcription factor binding sites for transcription factors in 19 genes involved in pathogenesis of tuberculosis. Some common SNPs are rs1327474, rs755622, rs1801274, rs396991, rs5030737, rs1800451, rs1800450, rs3763313 rs3763313, rs9268494 and rs9268492 that have been found to play a role in disease. Presence of non-synonimous polymorphisms in coding region might affect the structure of protein, whereas polymorphisms in promoter region affect the level of gene products, consequently altering the susceptibility resistance to disease. Based on this prediction, we hypothesize that these genes play an important role in susceptibility to tuberculosis through an altered expression of gene product via the modication of transcriptional regulation of gene.
Introduction
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection is a major, global public health problem affecting one-third of the world population [1]. In 2007, there were 9.27 million new cases of tuberculosis and 1.3 million deaths [2]. Particularly in sub-Saharan Africa, the prevalence of TB is increasing dramatically with the rise of HIV pandemic. Uganda is one of the worlds 22 highest TB burden country, with an estimated annual risk of tuberculosis infection of 3% and an annual incidence of new smear positive TB cases of 9.2 per 1000 [3]. Pakistan ranks 7th in terms of TB burden [4]. Because of an increase in rates of drug resistant tuberculosis, including multi-drug (MDRTB) and extensively drug resistant TB (XDRTB), it is becoming increasingly difcult to treat and control disease in developing countries [5].
DNA sequence variation in both parasite and host have been known to play an important role in susceptibility to disease, and consequently an improve understanding of the host response to Mtb will facilitate the development of new vaccines and therapeutics [6]. A number of genes have been identied that are associated with tuberculosis development [6, 7]. Several candidate gene studies and genome-wide linkage association studies have been performed for investigating their role in disease risk [813]. The host genetic factors and susceptibility to tuberculosis has been extensively explored in various ethnic populations. Some important candidate genes like human leucocyte antigen alleles and non-human leucocyte antigen genes, such as cytokines and their receptors, chemokines and their receptors, pattern recognition receptors, solute carrier family 11A member 1, (natural resistance-associated macrophage protein 1) and purinergic P2X7 receptor gene polymorphisms, reects differential
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association with susceptibility to TB in different population [14]. This article presents some important host genetic polymorphisms in genes involved in host immune response and their role in susceptibility resistance to pulmonary tuberculosis (PTB). Furthermore, this review covers several published casecontrol studies including different genes and genome wide linkage in different population. Moreover, we have predicted 275 single nucleotide polymorphisms (SNPs) in transcription factor binding of 19 genes involved in pathogenesis of tuberculosis. The experimentally validated SNPs are highlighted in Table 1. All these SNPs are reported in db SNP database, and only those have been predicted that fall in the region of transcription factor binding sites (TFBS).
Table 1 List of SNPs found in the 5 upstream region extending from )3000 to +500 BP with respect to TSS in the gene involved in the tuberculosis pathogenesis (IFNGR1, IL-1B, IL1R1, ALOX 5, CARD 15, CD 209, Frizzled homolog 5 Drosophila (FZD5), IL-18, Interlukin 12 receptor beta 2, Lymphotoxin alpha (LTA), Lymphotoxin beta (LTB), PTPN 22, SP110, TLR 4, TLR2, WNT5A, TNF, VDR, NOS2A). Bold SNPs are experimently validated. rs10004467 rs10116253 rs10168222 rs10187268 rs10408865 rs10409294 rs1041981 rs10459953 rs1047898 rs10553050 rs10560589 rs10560590 rs10601145 rs10664363 rs10759931 rs10759932 rs10875696 rs10983755 rs11102689 rs11168296 rs11209045 rs11214105 rs11239494 rs11297581 rs11329294 rs11329295 rs11329306 rs11343699 rs11395090 rs11433379 rs1143623 rs1143624 rs1143627 rs1143628 rs11465355 rs11465357 rs11465360 rs11465362 rs11465363 rs11465364 rs11465365 rs11465366 rs11465367 rs11465368 rs11536861 rs11544762 rs11574002 rs11574003 rs11574004 rs11574005 rs11574008 rs11574009 rs11574012 rs11575936 rs11576006 rs11679983 rs11707296 rs11710229 rs11805450 rs12024929 rs12142823 rs12142823 rs12199078 rs12264166 rs12351464 rs12356668 rs12356668 rs12359811 rs12378184 rs12497254 rs12525508 rs12720460 rs12720460 rs12720463 rs12762303 rs12812972 rs1293344 rs1327473 rs1327474 rs13374580 rs13426951 rs16826884 rs16944 rs17109841 rs17129717 rs17129718 rs17129719 rs17129722 rs17129726 rs17129728 rs17129733 rs1799765 rs1799916 rs1800195 rs1800610 rs1800630 rs1800683 rs1800919 rs181720 rs187238 rs1896260 rs1927914 rs1946518 rs1946519 rs2009658 rs2066850 rs2071590 rs2076752 rs2099683 rs2228088 rs2234650 rs2234652 rs2239704 rs2307151 rs2314814 rs2405433 rs2471961 rs2488457 rs2507961 rs2515924 rs2516312 rs2649867 rs2649868 rs2682448 rs2682449 rs2708920 rs2708921 rs2736195 rs2736196 rs2737193 rs2737194 rs2779249 rs2779249 rs2779249 rs2779250 rs2844482 rs2857706 rs2857711 rs2857712 rs2857713 rs2857713 rs2871448 rs2904614 rs3018465 rs3087258 rs3093540 rs3093541 rs3093544 rs3093546 rs3093547 rs3093548 rs3093549 rs3093550 rs3093551 rs3093562 rs3093563 rs3093661 rs3179060 rs360719 rs3762315 rs3762316 rs3762317 rs3789612 rs3834764 rs3917345 rs3917346 rs3917347 rs4141631 rs4141632 rs4141633 rs4248157 rs4248158 rs4248159 rs4248160 rs4248161 rs4248162 rs4248163 rs4248164 rs4516035 rs4645834 rs4645836 rs4645838 rs4645839 rs4647173 rs4647174 rs4647175 rs4647176 rs4647178 rs4647179 rs4647180 rs4647181 rs4647189 rs4647191 rs4647194 rs4647195 rs4647198 rs4785224 rs4804804 rs4987086 rs4987105 rs4987106 rs5021469 rs5743259 rs5743262 rs5743263 rs5743264 rs5743266 rs5743266 rs5743267 rs5744223 rs5744224 rs5744225 rs5744226 rs5744227 rs5744229 rs5833463 rs5833464 rs5833465 rs5833466 rs5833467 rs5833468 rs5833469 rs5833469 rs5875327 rs589557 rs5900307 rs590386 rs6478317 rs6593482 rs6708048 rs6710598 rs6743326 rs6743330 rs6743338 rs6758647 rs6761218 rs6761220 rs6761237 rs6761245 rs6761335 rs6761336 rs6831031 rs7139166 rs735239 rs735240 rs7359874 rs736160 rs7381804 rs7548827 rs7556811 rs7556903 rs760363 rs7758790 rs7765227 rs7766988 rs7866214 rs7913948 rs8046608 rs8111321 rs8112852 rs893629 rs893630 rs909253 rs915654 rs9267499 rs9267500 rs9267501 rs9279357 rs9279358 rs9281526 rs9282875 rs9380263 rs956730 rs9890573 rs9895793
Tumour necrosis factor-alpha (TNF-a) polymorphisms

Although the involvement of host genetic factor(s) is crucial; several host immune response genes are also engaged in determining susceptibility towards developing the active form of tuberculosis [15, 16]. TNF-a and lymphotoxin-a (LT-a) genes located within the MHC III region of chromosome 6 not only shows close linkage to the HLA class I (HLA-B) and class II (HLA-DR) genes but are also involved in the pathogenesis of tuberculosis due to its role in the formation and maintenance of granulomas [17]. Moreover, it also plays a major role in host defence to Mtb by its synergistic action with interferon-c (IFN-c) to activate macrophages and thereby affects disease perpetuation [18]. Elevated serum TNF-a (sTNF-a) levels have been reported in advanced tuberculosis patients compared with those with mild tuberculosis and healthy controls. Several promoter polymorphisms of TNF-a and intron 1 polymorphism of LT-a have been associated with altered levels of TNF-a [19, 20]. Some of these polymorphisms have been reported in several ethnic groups [2126]. Correa et al. [27] detected TNF-a gene polymorphisms ()308 and )238) in controls and patients of several diseases (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjogrens syndrome (SS) and tuberculosis. TNF -308G was associated with TB whereas )308 GG genotype was protective for autoimmunity. TNF-238A allele was protective for autoimmunity, but acted as a susceptibility factor for TB. Haplotype -308A-238G have been reported as a protective factor for TB, but susceptibility factor for RA, SLE and primary SS. Opposite association of TNF polymorphism with autoimmunity and TB, suggests that autoimmune diseases are a consequence of natural selection for enhanced TB resistance. Ates et al. [21] identied TNF-a ()308 G A, )238 G A, )376 G A) and IL10 ()1082 G A, )819 C T, )592 C A) polymorphisms in patients with TB and healthy controls. A signicant association was found between TB and )1082 G allele.
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Signicant difference was observed in IL10 GCC and ACC haplotypes distribution between TB cases and controls. No signicant association was found between IL-10 )819 C T, TNF-a, 308 G A, )238 G A, )376 G A polymorphisms and tuberculosis. Sharma et al. [20] performed a casecontrol study including TNF-a gene ()1031, )863, )857, )308, )238) and LT-a gene (+252) polymorphisms in North-Indian population. No signicant differences of the allele frequencies between the tuberculosis patients and controls were reported. All the polymorphisms included in their study did not give a signicant association with any of the patient subgroups; but observed a signicant difference in the serum TNF-a level in patients and controls.
ALOX5 polymorphisms
ALOX5 gene encodes 5-lipoxygenase (5-LO) that plays a key role in the biosynthesis of leukotrienes (LTs) and lipoxins (LXs) from arachidonic acid. Leukotrienes and lipoxins are involved in the generation of appropriate responses to inammatory disease as well as in the regulation of immune cells and release of cytokine [28]. Phagocytosis of microorganisms by alveolar macrophages and polymorphonuclear leukocytes (PMN) was dependent on LTB4, a class of LXs [29, 30]. A T-helper cell type 1 immune response is supported by enhanced production of interferon (IFN)-c and interleukin (IL)-12 [28, 31]. The anti-inammatory properties of LXs antagonize those of LTs in innate immunity by inhibiting PMN and natural killer (NK) cell functions, suppressing IL-12 release [31] and modulating the immune response by stimulation of IL-4 production [32], while blocking IL-5 and IL-13 and inhibiting eosinophil effector functions [33]. A casecontrol study by Herb et al. [34] included a variable number of tandem repeats (VNTR) in promoter and an exonic non-synonymous variant g.760G>A polymorphisms in TB patients and controls from Ghana. Carriers of one variant and one wild-type VNTR allele (n = 5) or of the exonic allele g.760A had a higher risk of TB. The association was strongest with TB for the non-5 760A haplotype as compared to non-5 760G haplotype.
CalmetteGuerin (BCG), Helicobacter pylori, Klebsiella pneumoniae, Streptococcus pneumoniae, HIV-1, HIV-2, SIV-1, Dengue virus, Ebola Virus, Cytomegalovirus, Hepatitis C virus, Schistosoma mansoni, Leishmania pifanoi and Candida albicans [3639]. The contribution of CD209 polymorphisms is important in human susceptibility to infectious diseases including M. tuberculosis and M. leprae, HIV-1 and Dengue [40, 41]. CD209 )336A G (rs4804803) promoter polymorphism has been associated with infectious disease susceptibility or protection in M. leprae. Martin et al. [42] demonstrated the )336G allele association with susceptibility to parenteral, but not mucosal HIV-1 infection, although this was not replicated in individuals of recent African descent. Vannberg et al. [43] investigated the role of the CD209 )336A G polymorphism and susceptibility to tuberculosis in subSaharan Africans. Signicant protection was observed with CD209 )336G variant allele in individuals from sub-Saharan Africa and cases with )336GG were signicantly less likely to develop tuberculosis-induced lung cavitation. Therefore, it has been suggested that decreased levels of the DC-SIGN receptor may be protective against both clinical and cavitory tuberculosis.
SP110 and CARD15 polymorphisms

Ipr1 gene is attributed to tuberculosis susceptibility in mice. Polymorphisms in the human homologue, SP110, explored in various populations revealed in only one isolated case, an association with TB susceptibility. Eight SP110 polymorphisms including two novel polymorphisms in a South African population, revealed no signicant association with any of these polymorphisms, including two polymorphisms that were previously found to be associated with TB susceptibility in West African populations [44]. Caspases recruitment domain-containing protein 15 (CARD15) genes encode the nucleotide-binding oligomerization domain 2 (NOD2) proteins and are considered as susceptibility gene for Crohns disease (CD). As a candidate gene in tuberculosis, its product NOD2 has been recognized as a non-redundant recognition mechanism of Mtb. Moller et al. [45] genotyped the R702W, G908R and 1007fs variants in TB cases and controls from the admixed South African coloured population and failed to nd statistically signicant differences between cases and controls for these variants. Earlier these polymorphisms have been reported to be associated with CD. Thus, the CD-associated mutations occur at very low frequencies in this population and CARD15 is not a major susceptibility gene for TB in the South African Coloured.
CD209 polymorphism
CD209 on chromosome 19p13.3 encodes Dendritic CellSpecic ICAM3-Grabbing Non-integrin (DC-SIGN), a C-type lectin, expressed on subsets of dendritic cells (DCs) and alveolar macrophages [35, 36]. DC-SIGN has the ability to bind a variety of endogenous ligands including endothelial cells through ICAM-2, T-lymphocytes through ICAM-3, neutrophils through MAC-1, various endogenous glycosylated structures [37, 38] and exogenous ligands such as glycosylated moieties on Mycobacterium leprae, Mycobacterium tuberculosis, Bacillus
BTNL2 polymorphisms
Butyrophilin-like2 gene (BTNL2) gene, a MHC class II gene-linked butyrophilin family member has recently
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been associated with diseases, such as tuberculosis, sarcoidosis and leprosy. As a candidate gene for tuberculosis in the South African Coloured population, 18 SNPs genotyped in BTNL2 gene in cases with PTB failed to establish a signicant association between the truncating rs2076530 SNP, previously associated with sarcoidosis and tuberculosis [46]. Furthermore, neither of the SNPs showed an association with disease nor the predicted haplotypes had any association with TB. Comparative analyses of the data from South African, German and American populations revealed that, for a segment of BTNL2, the admixed, but not stratied, South African population resembles the African-Americans more than white populations. Six SNPs of BTNL2 gene in tuberculosis cases in Chinese Han population did not reect any signicant association between any of these polymorphisms and TB, including rs2076530 SNP that was previously found to be associated with sarcoidosis [47]. Genetic study revealed a signicant association between the rs3763313, rs9268494, rs9268492 SNPs in the BTNL2 gene and tuberculosis. Haplotypes 15, and 8 (C A G T G A, C A G T G G, C A T G C A, C A T G C G, and C G T G C G, T A T G C A) presented a signicant association with susceptibility to tuberculosis.
IL1 B, IL4, IL10, IL12B, IL12RB, IL12RB2, IL18, IFN-c WNT5A, FZD5 gene polymorphisms
Interferon gamma is a major macrophage-activating cytokine, during M. tuberculosis infection and genes involved in the regulation of inammatory cytokine, interferon gamma may inuence susceptibility towards tuberculosis. Moller et al. [48] investigated 54 polymorphisms in eight candidate genes viz., interleukin 4 (IL4), interleukin 10 (IL10), interleukin 12B (IL12B), interleukin 12 receptor beta 1 (IL12RB1), interleukin 12 receptor beta 2 (IL12RB2), interleukin 18 (IL18), wingless-type MMTV integration site family, member 5A (WNT5A) and frizzled homolog 5 (FZD5) in tuberculosis cases and healthy individuals in South African population. A functional SNP (rs2243250, IL-4 -C590T), was associated with increased promoter strength, stronger binding of transcription factors and with different levels of IL-4 activity, but un-associated with TB [49, 50]. The CC genotype of this polymorphism was previously associated with protection against pulmonary TB in south Indian, Russian, but not in Gambian populations [5153]. Two polymorphisms )511 and +3953 in IL1B and one in the IL1RN, 86 bp VNTR in smear positive TB patients, and control in Gambians (all HIV negative) were explored and decreased risk of pulmonary TB was associated with both heterozygosity and homozygosity for the IL1B )511-C allele. No association existed between the IL1B+3953-T C polymorphism or the 86 bp IL1RN pentallelic repeat and TB in this population. Using an ex-vivo whole blood assay,
healthy Gambian individuals who were homozygous for IL1B )511-T allele failed to exhibit a signicant increase in IL-1b production in response to LPS after IFN-c priming. IFN-c plays a central role in the modulation of tuberculosis disease severity as it is involved in host immune response against M. tuberculosis infection. The 12 CA repeat microsatellite allele in the non-coding region of the rst intron is associated with a high level of in vitro cytokine production [54]. In a recent study, polymorphism at position +874 is associated with risk of tuberculosis in different population [55, 56]. Ansari et al. [4] found that the ratio of two key cytokines (IFN-c and IL10) exhibited signicant correlation with the severity spectrum of tuberculosis in Pakistani population. Furthermore, the frequency of cytokine gene polymorphism is linked to high and low responder phenotypes (IFNc +874 T A and IL10 )1082 G A) in tuberculosis patients. These ndings are consistent with the role of IL10 in reducing collateral tissue damage and the protective role of IFNc in limiting disease in the lung. A+874T polymorphism on the intron-1 of IFNc gene, associated with the secretory capacity of IFNc, was found to be associated with the development of TB among Sicilians, South Africans, Hong Kong Chinese and Spanish, [5761] and interestingly this association was not found in Malawians [54] and in populations from Houston, [59] West Africa [59] South India [61] and China [62]. A recent study of 77 TB patients from Japan revealed that the IFNG + 874 AA genotypes were strongly and independently predictive of a lower likelihood of sputum conversion. Etokebe et al. suggested an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population. Upon investigating two IFNG SNPs (T+874A and G+2109A) in patients (n = 253) hospitalized in Rijeka (Croatia) and ethnically matched controls (n = 519) they suggested that patients had signicantly higher frequency of genotypes without T at +874 (AA AA; AA AG and AG AG) in microscopy or bacterial culture-positive groups as compared with their negative counterparts [63]. IL-12 is a heterodimeric pro-inammatory cytokine produced by monocytes, macrophages, DCs and B lymphocytes. SNP in the gene responsible to express this subunit was rst described by Hall et al. [64]. Several polymorphisms in promoter, introns and 3UTR in the IL-12B gene are associated with TB in various populations, although with inconsistent results. Polymorphisms in the coding sequence of the IL-12 receptor b1 gene have been associated with TB in Moroccan and Japanese populations, but not in Koreans. The IL-12B polymorphism is not correlated with susceptibility to tuberculosis in black and white North American population. Four SNPs, 641 A-G, 684 C-T, 1094 T-C and 1132 G-C can cause three missense variants (Q214R, M365T and
G378R) and one synonymous substitution in the extracellular domain of the IL-12Rb1 gene. The association of R214-T365-R378 allele (allele 2) is over-expressed in Japanese tuberculosis patients with the homozygosis for R214 - T365 - R378 (the 2 2 allele) being signicantly associated with tuberculosis.
Interferon-c receptor-1(IFNcR1) polymorphisms

Human interferon-gamma receptor is a heterodimer of IFNcR1 and IFNcR2. Genetic variations in IFNcR1 are associated with susceptibility to H. pylori infection. In addition, defects in IFNcR1 may further result in Mendelian susceptibility towards mycobacterial disease commonly known as familial disseminated atypical mycobacterial infection. Several SNPs in IFNcR1 have been investigated in falciparum malaria cases and controls. The frequencies of IFNcR1 promoter polymorphisms (G-611A, T-56C) in tuberculosis patients and controls are not signicantly different. In studies where SNP affect transcription, the expression of IFNcR1 gene does not confer susceptibility to disease in patients from Croatia [65]. A signicant association exists between the protective (CA)n polymorphism (22 repeats, 192 FA1), located in intron ve of the IFNcR1 gene and GT promoter haplotype ()611; )56) that showed the strongest expression capacity. In addition to this cis relationship, the (CA) 22 allele was correlated in trans with an IFN-c SNP (IFNc G2109A), which might affect the transcription of the IFNc gene. Thus, a particular combination of IFNc and IFNcR1 SNP (gene-gene) interaction might provide a better protection against tuberculosis in this population. Several families with Mendelian susceptibility to mycobacterial disease have also been explored that has mutations in one of two subunits of the IFN-c receptor gene (IFN cR1 and IFN cR2) [66]. The polymorphisms identied in Gambians were at +95, )56 and )270 nucleotides and a TT deletion at )470 )471 nucleotides. No association was observed for any of these polymorphisms with PTB in Gambians.
NOS2A polymorphisms
Nitric oxide (NO) acting as a free radical and second messenger have been implicated in the development of several diseases, including tuberculosis. NO, produced by NOS2A, plays a major role in pulmonary host-defense mechanism and is involved in bacteriostatic as well as bactericidal processes. Cytokines like, TNF-a, IL-1b along with IFN-c produced by T cells can induce NO via action of NOS2A. It has been proposed that NO produced by tuberculosis-infected human macrophages and by epithelial cells is anti mycobacterial against M. tuberculosis [67]. The alveolar macrophages from the lungs of patients with tuberculosis express NOS2A in potentially
mycobactericidal amounts which can kill mycobacterium [68]. We have reviewed the role of three SNPs ()954G C, )1173C T, )1659 A T), one microsatellite repeat in promoter and one SNP in exon 16 of gene in several casecontrol studies [69]. The promoter polymorphisms ()954G C, )1173C T, )1659 A T) have been shown to increase NO synthesis [70]. This region in the human gene is situated from )0.7 to )2.6 kb upstream of the transcription start and contains important DNA motifs for binding of NF-jB, activator protein1, signal transducer and activator of transcription protein 1, and NFjB repressing factor [71]. The )954G C variant was originated as a consequence of selective pressure of Plasmodium in endemic area of Africa. The G allele was absent from Caucasian populations [72] as well as from the Peruvian population [73] whereas in Mexicans, the G allele was not associated with tuberculosis [74]. Two genes, NOS2A and CCL2 on chromosome 17 play a role in susceptibility to tuberculosis in South African population [75]. Haplotype of two functional (rs9282799 and rs8078340) SNPs in the NOS2A promoter have been signicantly associated with tuberculosis. Presence of T allele decreases the DNA-protein complex formation and the duration of DNAprotein interaction, which leads to decrease NO production. The T allele of SNP rs8078340 is over represented in the patients. As NO possess potent antimicrobial effects, having ability to inhibit the growth of many infectious organisms in vitro, polymorphism in the promoter alters the level of NOS2A, decreasing the level of NO and thereby increases the susceptibility to tuberculosis. Velez et al. [76] performed casecontrol association study of TB patients and controls in African-Americans and Caucasians. Thirty-nine SNPs were selected from the NOS2A gene, for single SNP, haplotype, and multilocus interaction analyses with other typed candidate genes. In African-Americans, ten NOS2A SNPs were associated with TB. The strongest associations were observed at rs2274894 and rs7215373. The strongest genegene interactions were between NOS2A rs2248814 and IFNGR1 rs1327474 and NOS2A rs944722 and IFNGR1 rs1327474. Three other SNPs in NOS2A interacted with TLR4 rs5030729 and ve other NOS2A SNPs interacted with IFNGR1 rs1327474. Interestingly, no signicant associations existed in Caucasians. These results suggested that NOS2A variants may contribute to TB susceptibility, particularly in individuals of African descent, and may act synergistically with SNPs in TLR4 and IFNGR1.
Vitamin D receptor (VDR) polymorphisms

The VDR gene is one of the most important candidate genes that play a role in susceptibility to tuberculosis. Preto investigated genetic polymorphisms of vitamin D, VDBP, TLR, NOS2A and IFN-c genes and resistance or
susceptibility to M. tuberculosis infection [77]. Polymorphisms that affect the activity of the receptor have profound impact. Genetic variants of the natural resistance-associated macrophage protein (NRAMP1) and vitamin D receptor (VDR) genes are associated with smear-positive PTB in Gambian [78, 79]. VDR genotypes exhibited differential susceptibility or resistance to tuberculosis. The inuence of FokI, BsmI, ApaI and TaqI variants of VDR gene on 1, 25(OH)(2) D(3) modulated granzyme A expression of cytotoxic lymphocytes induced by culture ltrate antigen (CFA) of Mtb [80]. The ApaI aa genotype and bbaaTT extended genotype were associated with a signicantly decreased percentage of granzyme A positive cells in normal healthy controls. The study suggests that 1, 25(OH)2D3 suppresses granzyme A probably by downregulating Th1 cytokine response. Gao et al. [81] has reviewed VDR polymorphisms and TB susceptibility and quantitatively summarized associations of the polymorphisms (FokI, TaqI, ApaI and BsmI). Among Asians, the FokI ff genotype showed a pronounced positive association; a signicant inverse association was observed for the BsmI bb genotype and for TaqI and ApaI polymorphisms associations were marginal. None of the polymorphisms studied showed signicant association to TB among Africans or South Americans.
Also, the frequency of Gc2 in tuberculosis patients was slightly, but not signicantly higher than in the control group and this elevation were at the expense of both Gc1F and Gc1S alleles [85].
Natural resistance-associated macrophage protein (NRAMP1)

Li et al. [86] performed a meta-analysis in East-Asia population. A total of 1067cases and 1084controls in eight publications were included in the study; all genotype frequencies were consistent with HardyWeinberg equilibrium. The summary of Odd ratios (ORs) for studies with polymorphisms of 3 UTR, D543N and INT4 loci of the NRAMPI gene among the East-Asia population were 1.68 (95% CI: 1.312.16, P < 0.001), 1.78 (95% CI: 1.382.30, P < 0.001), 1.56 (95% CI: 0.723.35, P = 0.26), respectively when compared with their corresponding common homozygotes. The cumulative summary effects ORs were 1.85 (P = 0.02) in 2000, 1.35 (P = 0.12) in 2002, 1.64 (P = 0.001) in 2003 and 1.68 (P < 0.001) in 2004 for 3UTR locus, 1.88 (P = 0.001) in 2000, 1.65 (P = 0.001) in 2002, 1.70 (P < 0.001) in 2003, 1.76 (P < 0.001) in 2004, and 1.78 (P < 0.001) in 2005 for D543N locus, and 0.88 (P = 0.70) in 2002, 2.50 (P = 0.41) in 2003, 1.52 (P = 0.42) in 2004 and 1.56 (P = 0.26) in 2005 for INT4 locus [86] have been reported. Although the natural resistance-associated macrophage protein (NRAMP1), vitamin-D receptor (VDR) and TNF-a have been associated with susceptibility to tuberculosis, the results have been inconsistent [87]. This study determines the association of NRAMP1, VDR, and TNF-a variant with development of PTB among Iranian patients. The SNPs at INT4, D543, 3UTR of NRAMP1 gene, in restriction sites of BsmI, and FokI of the VDR gene and SNPs of TNF-alpha at )238, )308, )244, 857, )863 positions were analysed. Although, no statistically signicant differences were observed in allele frequencies of INT4, D543, 3UTR of NRAMPI, FokI of VDR and TNF-alpha at )238, )244, )863 and )857 position. However the frequency of b allele of BsmI [ORs: 0.24 CI: 95% (0.070.67 (P = 0.001)] and )308 A variant in TNF-alpha promoter region [ORs: 0.26 CI: 95% (0.070.77) (P = 0.006)] were signicantly more in PTB patients than healthy controls. Natural resistance associated macrophage protein1 (Nramp1 Slc11a1) gene has been associated with mycobacterium infection [88]. To determine the association of Nramp1 Slc11a1 with tuberculosis and leprosy, analysis was performed using restriction fragment length polymorphisms of three variants (D543N, 3UTR and INT4) of Nramp1 Slc11a1 gene in 58 tuberculosis patients, 42 leprosy patients and 198 healthy controls from South Sulawesi, Indonesia. An association of INT4 polymorphism
Vitamin D-binding protein (VDBP)

VDBP encoded by Gc gene is a multifunctional, highly expressed, polymorphic serum protein. It is the major plasma carrier of vitamin D3 and its metabolites, ensuring that vitamin D is transported to the liver, 25(OH)2D3 to kidney and 1, 25(OH)2D3 to target cells and organs. A multigene cluster on chromosome 4q11-q13 includes albumin, a-fetoprotein and Gc gene. Variations in exon 11 of the Gc gene at codons 416 and 420 give rise to electrophoretic variants of VDBP, called Gc1 fast (Gc1F), Gc1 slow (Gc1S) and Gc2 differing by amino-acid sequence, as well as by the glycosylation pattern. Combination of the three VDBP or Gc variants result in six common circulating phenotypes: Gc1F Gc1F, Gc1F Gc1S, Gc1S Gc1S, Gc1F Gc2, Gc1S Gc2 and Gc2 Gc2 [23]. DBP polymorphism (Gc phenotype) is related to the VDBP concentration and the status of vitamin D [82]. A strong correlation of higher, intermediate and lower circulating levels of 25(OH)2D3 and 1,25(OH)2D3 with Gc1-1, Gc1-2 and Gc2-2 phenotypes, respectively, existed in Danish Caucasian post-menopausal women. Variations in this property could affect the functioning of the immune system, as DBP knockout mice exhibited an impaired immune response to bacterial infections [83]. A possible role has been suggested of DBP polymorphism in autoimmune diabetes mellitus and infectious disease in Polynesia and Japan [84]. No difference in DBP phenotype was seen among patients and the control group.
with paucibacillary type of leprosy (P = 0.032, 1 df, OR = 2.975, CI = 1.0578.373), but not to multibacillary type (P = 0.173, 1 df, OR = 2.248, CI = 0.682 7.404) have been observed. No signicant association was found in these three variants with tuberculosis in this population.
The Toll-like receptors (TLR)

TLR represents a group of single-pass transmembrane receptors which are expressed on innate immune cells; function as sensors for pathogen-derived molecules and plays role in hostpathogen interaction [89]. TNF-a and NO are induced mostly by macrophages soon after innate recognition of mycobacterium through TLRs [90]. The role of TLR in resistance to M. tuberculosis was initially suggested by the fact that MyD88-decient mice are more susceptible to M. tuberculosis infection [91] and by the observation that TRL2 TLR1 reduced the viability of intracellular M. tuberculosis in human monocytes and macrophages, but not in monocyte-derived DCs [92]. The human TLR2 gene is located on chromosome 4q32 and is composed of two non-coding and one coding exon [93]. In TLR2 gene, 89 SNPs have been reported, (26 in the 5-untranslated region, 17 in the 3-untranslated region, 29 located in intronic parts of the gene and 17 modify bases of the third exon of TLR2). Six non-synonymous SNPs of the TLR2 gene change amino acids in the cytosolic part of this receptor, out of which, only two have been linked to reducing NF-jB activation and increasing the risk of infection. The rst SNP change of C to T replaces arginine (Arg; R) with tryptophan (Trp, W) at position 677 and abolishes the binding of MyD88 with TLR2. Further, this specic polymorphism located within the bb loop of TLR2 (Arg677Trp) abolishes activation of NF-jB in response to M. tuberculosis, consequently decreasing IL-12 serum level production by 677W carriers [94]. The second TLR2 SNP changes G to A, which substitutes an arginine for glutamine at position 753. The TLR2 753Q seems to be associated with an increased risk of developing tuberculosis for carriers of the AA and AG genotypes [95]. Thuong et al. [96] described a strong association of SNP T597C TLR2 with susceptibility to military tuberculosis patients from Vietnam. Further association was described among Koreans regarding the microsatellite polymorphisms in intron II or TLR2 [97]. In addition, TLR1 polymorphism in a non-synonymous region (I602S) could be associated with TLR1 2 heterodimer binding sites to mycobacterial lipopeptide, as individuals with 602II genotype produced substantially more IL-6 than those with the 602SS variant [98]. Currently, the polymorphism in TLR2 might be an important risk factor for disease progression. The G to A (Arg753Gln) polymorphism at position 2258 in exon 3 and the guanine-thymine (GT) microsatellite repeat polymorphism
(100 bp upstream of the translational start site) in intron 2, have been associated with susceptibility to clinical tuberculosis (TB) disease in Turkish and Korean patients respectively [90, 92]. TLR2 promoter region, namely, )16934 A>T and )196 to )174 insertion (Ins) >deletion (Del) polymorphisms have been associated with asthma and gastric cancer respectively [99, 100]. Patients with pulmonary TB and healthy controls examined for TLR2 polymorphisms over locus )100 (microsatellite guanine-thymine repeats), )16934 (T>A), )15607 (A>G), )196 to )174 (insertion>deletion), and 1350 (T>C) [101] exhibited an association between the haplotype (A-G-(insertion)-T) and susceptibility to pulmonary TB. As opposed to TB patients without systemic symptoms, lower )196 to )174 deletion deletion genotype frequency existed in patients with systemic symptoms for TB. Moreover, such patients with the deletion deletion genotype had higher blood NK cell counts than those carrying the insertion allele. TB patients with pleuritis had a higher 1350 CC genotype frequency than those without pleuritis. Also, TB patients with the 1350 CC genotype had higher blood NK cell counts than those carrying the T allele. The patients of TB carrying homozygous short alleles for GT repeats had higher blood NK cell counts than those carrying one or no short allele. Thus, an association exists between the specic TLR2 haplotype and susceptibility to pulmonary TB. In patients with pulmonary TB, both the )196 to )174 Del Del and 1350 CC genotypes were associated with an increased blood absolute NK cell counts. Toll-like receptor 2 (P631H) mutants impairs membrane internalization and is a dominant negative allele. Etokebe et al. [102] sequenced 416 Toll-like receptor-2 (TLR2) alleles in 208 subjects in Croatian Caucasian population and found 10 SNPs, among which three were novel (S97S, T138I and L266F). Their ndings reect that TLR2-P631H allele could be associated with susceptibility to tuberculosis.
Toll-like receptor 4 polymorphism

Toll-like receptor 4 plays an important role in the innate immunity against tuberculosis. Ildefonso et al. [103] analysed the association between TLR4 Asp299Gly and Thr399Ile SNPs and active TB, in Caucasian Mediterranean HIV-infected individuals. Asp299Gly were independently associated with active TB and inversely with latent TB prophylaxis. An independent association seems to operate between TLR4 Asp299Gly SNP and active TB in Caucasian Mediterranean HIV-infected patients.
Toll-like receptor 8 polymorphisms

Davila et al. [104] studied TB association and expression of 18 genes involved in the TLR pathways in pulmonary TB patients and controls from Indonesia. In the TLR8
gene, four polymorphisms on chromosome X showed evidence of association with TB susceptibility in male patients, including a non-synonymous polymorphism rs3764880 (Met1Val). Further, on genotyping these four TLR8 polymorphisms in an independent collection of pulmonary TB patients and controls from Russia an evidence of association existed in male patients (for rs3764880). There is also a marked increase in TLR8 protein expression in differentiated macrophages upon infection with Mycobacterium bovis, BCG. A role for the TLR8 gene has been in susceptibility to pulmonary TB across different populations. Polymorphisms (1805 G T in TLR1, 2258 A G in TLR2, )857 C T and )863 A C in TNF-a and )819 C T in IL-10) genotyped in tuberculosis patients and controls [105] and multivariate logistic regression analysis revealed that the TT genotype of )857 C T in TNF-a gene was signicantly associated with lower risk of PTB, in comparison with other genotypes. The genetic variant of )863 A C in TNF-a gene was associated with susceptibility to PTB and clinical severity of disease. The study suggested that the variants in TNF-a gene were associated with susceptibility to PTB and clinical severity of disease, whereas no signicant association exists for TLRs and IL-10 gene polymorphisms and tuberculosis.
MIF, FCGR2A and FCGR3A gene polymorphisms

An analysis was carried out of the polymorphisms of macrophage migration inhibitory factor (MIF), Fcg receptors CD16A (FCGR3A) and CD32A (FCGR2A) genes and susceptibility to PTB in the Moroccan population [106]. The genotyping for MIF-173 (G C) (rs755622), FCGR2A-131 H R (rs1801274) and FCGR3A-158V F (rs396991) revealed a statistically signicant increase of the MIF )173CC homozygote genotype and MIF )173*C allele frequencies in PTB patients compared with healthy controls. In contrast, no association was observed between FCGR2A-131H R and FCGR3A158V F polymorphisms and tuberculosis disease. These nding indicates that MIF )173*C variant may play an important role in the development of active tuberculosis.
CCR2, MCP-1, SDF-1a & DC-SIGN gene polymorphisms

Chemokine, chemokine receptor and DC-SIGN gene polymorphisms were associated with susceptibility resistance to HIV and HIV-TB in south India [109]. CCR2 V64I (G A), monocyte chemoattractant protein-1 (MCP1) )2518 A G, stromal cell derived factor-1alpha; (SDF1alpha) 3UTR G A and DC-SIGN gene polymorphisms were explored in HIV-1 infected patients without TB, with pulmonary TB (PTB) and extrapulmonary TB, PTB patients without HIV and healthy controls. No signicant differences in genotype frequencies of CCR2 V64I, MCP-1 )2518 and DC-SIGN polymorphisms were observed between the study groups. Signicantly increased frequency of GG genotype of SDF-1alpha polymorphism was observed among positive for HIV and PTB patients compared with healthy controls. The GG genotype of SDF-1alpha 3UTR polymorphism may be associated with susceptibility to PTB in HIV-1 infected patients. Raghavan et al. [110] detected the HLA-DR2 subtypes and the possible HLA-A -B -DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with PTB (HIV+PTB+). Over representation of HLA-DRB1*1501 in HIV+PTB) patients and DRB1*1502 in HIV+PTB+ patients as compared with healthy controls was detected. There was an increased frequency of HLA-A2-DRB1*1501 haplotype in HIV+PTB) patients and HLA-A2-DRB1*1502 among HIV+PTB+ patients compared with healthy controls. The study suggests that HLA-A2-DRB1*1501 haplotype may be associated with HIV infection whereas HLA-A2DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. HLA-B40-DRB1*1501 and HLA-B40-DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients [110].
PTPN22 gene polymorphism

PTPN22 gene encodes the lymphoid tyrosine phosphatase that has an important regulatory effect on T- and B-cell activation in immune response. Lamsyah et al. [106] reported an association of PTPN22 gene functional variants with development of PTB in Moroccan population. A study of two missense polymorphisms of the PTPN22 gene (R620W and R263Q) and susceptibility to TB in the Moroccan population revealed a statistically signicant difference in the distribution of the PTPN22 1885T allele between pulmonary TB patients and healthy controls. In case of PTPN22 R263Q (G788A) SNP, there was an increase of 788A allele frequencies in TB patients compared with those in healthy controls. These results support the view that PTPN22 gene variants may affect susceptibility to TB in the Moroccan population.
Human V-ATPase polymorphism

Capparelli et al. [107] tested polymorphisms in the intron 15 and the 5-untranslated region of the gene coding for the a3 isoform of the human ATPase gene in PTB patients and controls. Alleles (two at each site) segregated in the form of four haplotype pairs. The double heterozygous patients were protected against tuberculosis and the double homozygous patients were susceptible to the disease.
TIRAP polymorphisms and susceptibility to childhood TB

The adaptor protein TIRAP mediates downstream signalling of TLR2 and TLR 4. TIRAP gene polymorphisms have been associated with susceptibility and resistance to tuberculosis (TB) in adults in South Africa. Dissanayeke et al. [111] identied 13 SNPs, and found signicant differences in frequency of the variants between the two ethnic groups. The frequency of individual polymorphisms or combinations did not vary between TB cases and controls in either cohort. The 558C T polymorphism previously associated with TB meningitis (TBM) in a Vietnamese population was found to be associated with TBM in the mixed ancestry group. The study suggests that polymorphisms in TIRAP do not appear to be involved in childhood TB susceptibility in South Africa.
associated with increased TB risk in Malawi. Purinergic P2X7 receptors are cationic channels present on the cells in the blood and immune systems. A polymorphism with a 1513 A-C (rs3751143) that replaces the glutamic acid at residue 496 by alanine was not associated with pulmonary TB in Gambia [118]. Southeast Asian refugees in Australia had no association of the 1513 SNP with pulmonary TB, but a strong association exists between the C polymorphism and extrapulmonary TB [7].
Association analysis of susceptibility region on chromosome 5q31 for tuberculosis

In the Asian population, chromosome 5q23.231.3 has been identied as a region with linkage to tuberculosis [119]. A putative tuberculosis susceptibility locus was investigated, in a family-based association test between the dense SNP markers within chromosome 5q31 and tuberculosis in Thai trio families. Seventy-ve SNPs located within candidate genes covering SLC22A4, SLC22A5, IRF1, IL5, RAD50, IL13, IL4, KIF3A and SEPT8 were genotyped. Analysis revealed that the most signicant association with tuberculosis in haplotypes comprising SNPs rs274559, rs274554, and rs274553 of SLC22A5 gene, which remained signicant after multiple testing corrections. The two haplotypes within the SLC22A4 and KIF3A region were associated with tuberculosis. Haplotypes of SLC22A5 were signicantly associated with the expression levels of RAD50 and IL13. The variants carried by the haplotypes of SLC22A4, SLC22A5 and KIF3A region potentially contribute to tuberculosis susceptibility among the Thai population.
Mannose-binding lectin polymorphisms

Mannose-binding lectin (MBL) is considered as an important component of innate immunity. Four functional MBL2 alterations in codons 52, 54, 57 and in the promoter at position c.1-290 are correlated with signicantly lower MBL serum levels. These variants have been associated with susceptibility to a variety of infectious agents as well as with various immunologic disorders. The gene encoding MBL is located on chromosome 10 and is designated as MBL2. MBL elicits complement activation by binding to mannose- and N-acetylglucosamine sugar groups on various microorganisms. Variations in the serum MBL levels are mainly due to the presence of three common point mutations in exon1 of MBL2 gene, at the codons 52 (rs5030737), 54 (rs1800451) and 57 (rs1800450). MBL deciency is an example of evolutionary selection, as MBL deciency reduces the capacity of mycobacterium to invade macrophages and consequently provides resistance to TB [112]. Variations at codons 52, 54 and 57 lead to low or near absent serum MBL. In a South African study it has been suggested that hetrozygotes for MBL54 have protection against tuberculosis meningitis [113]. TB patients as compared with controls have an increased genotype frequencies for mutant homozygotes at codons 52, 54 and 57 in South Indians, but no association has been reported in China [91], Poland [112], Turkey [113], Malawi [114, 115], Tanzania [116] and Gambia, [117].
Genome-wide analysis of genetic susceptibility to tuberculosis

Bellamy et al. [9] performed genome-wide analysis of genetic susceptibility to tuberculosis in Africans. A twostage genome-wide linkage study was performed to search for regions of the human genome containing tuberculosis-susceptibility genes. They used sibpairs families that contain two full siblings, affected by clinical tuberculosis. 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from Gambia and South Africa. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage to tuberculosis. These results indicate that genome-wide linkage analysis can contribute to the mapping and identication of major genes for multifactorial infectious diseases of humans. Thye et al. [120] identied a genetic variant, which increases susceptibility to tuberculosis (TB) in African
Complement receptor polymorphisms and Purinergic P2X7 receptor

The complement receptor-1(CR1) present on the surface of the macrophages is associated with phagocytosis of various microorganisms, including M. tuberculosis. Homozygotes, one in ve of CR1polymorphisms (Q1022H) are
populations. These studies involved analysing hundreds of thousands of genetic markers across the human genomes in search of variants found in patients, but not in healthy controls.
Polymorphism of 3UTR region of TNFR2 coding gene and its role in clinical tuberculosis
TNFR2 encoded by the TNFRSF1B gene is one of the important TNF-a receptors; its polymorphisms were earlier suggested as potential markers of host susceptibility to TB. Three SNPs in TNFRSF1B 3UTR (rs1061624, rs5030792, rs3397) was performed in Han Chinese paediatric population (229 TB patients and 233 control subjects). The rs5030792 was found homozygous (TT genotype) in all individuals [121]. The rs3397-T allele was almost equally represented in both gender groups in this study; in particular, it was detected in 33.9% and 35.2% in female cases and controls, respectively (P = 0.8). This latter result differs strikingly from an African study where rs3397-T was found in only 12.8 and 16.2% of Ghanaian female cases and controls, respectively (P = 0.007) [122]. In contrast, rs1061624-A allele, acting recessively, was a possible risk factor for clinical TB in females (P = 0.03). The rs1061624 heterozygotes were overdominant in controls versus patients (P = 0.015) that warrants further study of their hypothetical advantage in TB. Neither of the common haplotypes was associated with susceptibility to TB.
Table 2 List of transcription factors, which have transcription factor binding sites in the 5 upstream region extending from )3000 to +500 BP with respect to TSS in IFNGR1, IL-1B, IL1R1, ALOX 5, CARD 15, CD 209, Frizzled homolog 5 Drosophila (FZD5), IL-18, Interlukin 12 receptor beta 2, Lymphotoxin alpha (LTA), Lymphotoxin beta (LTB), PTPN 22, SP110, TLR 4, TLR2, WNT5A, TNF, VDR, NOS2A. AGL3 AML-1 ARNT Athb-1 ATHB5 Brachyury Broad-complex_1 Broad-complex_4 bZIP910 CF2-II CFI-USP Chop-cEBP COUP-TF CREB c-REL Dorsal_1 Dorsal_2 E2F E4BP4 E74A Evi-1 FREAC-4 Hen-1 HFH-2 HFH-3 HLF HMG-IY HNF-1 HNF-3beta Hunchback IL12RB2 Irf-1 Max MEF2 Myc-Max Myf NF-kappaB NF-Y n-MYC NRF-2 p65 Pax-4 Pax6 Pbx RORalfa-1 RREB-1 SAP-1 Snail SOX17 Sox-5 Spz1 SQUA Staf SU_h Tal1beta-E47S TBP TEF-1 Thing1-E47 USF
Methods
In Silico detection of DNA sequence variations modifying transcriptional regulation. DNA sequence variations (polymorphisms) affecting the expression levels of genes play important roles in the pathogenesis of diseases. We have identied several polymorphisms affecting the regulation of genes with the help of a web tool called regulatory analysis of variation in enhancers (RAVEN). This web tool is available at http://www.cisreg.ca. On entering the keywords, search engine gives a list of human gene. Click the gene of interest, genome location of gene is displayed by the software. Selection of the genomic regions from )3000 to 500 bp gives results in graphical and in tabulated forms. In the result view, we have option for analysis of SNPs with a particular transcription factor or the entire transcription factor. JASPAR: an open-access database for eukaryotic transcription factor binding proles. This software was developed by Andersen et al. [123] and results are shown in Tables 1 and 2.
Discussion
In human genome, different types of variations are reported such as copy number variations (CNV), micro 2012 The Authors. Scandinavian Journal of Immunology 2012 Blackwell Publishing Ltd.
satellite repeats (SSR) and SNP. Among them, SNPs is the most common type of variations. Presence of SNPs in coding region affects protein structure while the promoter region affects its level. Alteration in level or structure caused by DNA sequence variations have been shown to play a crucial role in development of active form of disease. Several host genes have been shown to contribute signicantly towards development of active tuberculosis [124]. As only a small percentage of infected individuals develop active form of disease, the difference in polymorphisms within genes involved in host immune response has been proposed as a possible reason to explain this phenomenon [104]. Although several mechanisms operate in gene regulation, transcriptional control seems to be crucial. Promoter hypermethylation and presence of polymorphisms in regulatory region are the two most important factors that interfere with the gene regulation and our hypothesis is that during disease conditions, there is up regulation or down regulation of gene (transcriptional dysregulation). In this context the infection of Plasmodium falciparum upregulates the expression of TNF-alpha which in turn increases the expression of adhesion molecules on the surface of blood vessels. Under conditions of certain cancers, there is down regulation of genes. GSTP1 expression is markedly decreased in various adenocarcinoma and prostatic intraepithelial neoplasia (PIN) specimens [125]. Promoter polymorphisms in TFBS (cis-elements)is an important factor that contributes to dysregulation of genes and thus plays a role in pathogenesis of tuberculosis. Promoter methylation interferes with gene expression as methyl group disrupts the interaction between transcription factors and TFBS. Several polymorphisms in TFBS of genes involved in pathogenesis of tuberculosis
578 DNA Sequence Variation and Regulation
T. Qidwai et al. ..................................................................................................................................................................
Table 3 Overview of various casecontrol studies including different genes in different populations of the word up to 2010. Gene name Tumour necrosis factor TLR4 Symbol LTA_NcoI; TNFA )238, )308, )857, )863, )1031 Asp299Gly SNP Disease type Lack of association with TB. Independent association Population North Indian Caucasian Mediterranean HIV-infected patients China References Sharma et al. [20] Ildefonso et al. [103]
Toll-like receptors, tumour necrosis factor-alpha, and interleukin-10 TLR2
1805 G T TLR1, 2258 A G TLR2, )857 C T, and )863 A C TNF-a )100 (microsatellite repeats), )16934 (T>A), )15607 (A>G), )196 to )174 insertion>deletion), and 1350 (T>C) TLR4 Asp299Gly and Thr399Ile rs3764880 (Met1Val) rs2076530 IL 12 B haplotypes
TNF-a associated with TB, no association of TLRs and IL-10 TB TLR2 variants play a role in the development of TB
Ma et al. [105]
China
Chen et al. [101]
TLR4 TLR8 BTNL2 IL4, IL10, IL12B, IL12RB, IL12RB2, IL18, WNT5A, FZD5 TLRs, TNF-a and IL-10
Association with TB Association with TB Association with TB A nominally signicant association Variants in TNF-a associated with susceptibility to PTB. no signicance with TLRs and IL-10 variants FokI ff genotype show positive association with TB & inverse association with BsmI bb genotype Affect susceptibility to TB Association with TB No association with TB No association withFCGR2A-131H R and FCGR3A-158V F variants while MIF )173*C variant play role in active TB HIV-TB PTB PTB
Caucasian Mediterranean Russia Chinese Han population South African
Ildefonso et al. [103] Davila et al. [104] Lian et al. [47] Moller et al. [45]
1805 G T in TLR1, 2258 A G in TLR2, )857 C T, TNF-a )863 & A C, )819 C T IL-10
Chinese
Ma et al. [105]
FokI, TaqI, ApaI and BsmI
Africans, South Americans
Gao et al. [81]
PTPN22 Arachidonate 5-lipoxygenase ALOX5 BTNL2 MIF, FCGR2A, and FCGR3A
Vitamin D receptor gene Vitamin D receptor 1, 25-dihydroxyvitamin D3 and vitamin D receptor gene variants Vitamin D receptor gene Vitamin D receptor gene Tumour necrosis factor Lymphotoxin alpha Tumour necrosis factor Tumour necrosis factor Tumour necrosis factor
R263Q (G788A), R620W (C1858T) 760G>A exonic, &a VNTR in promoter rs2076530 MIF-173 (G C) (rs755622), FCGR2A-131 H R (rs1801274), and FCGR3A-158V F (rs396991) VDR VDR VDR
Moroccan Ghana, West Africa South African Moroccan
Lamsyah et al. [106] Herb et al. [34] Moller et al. [46] Sadki et al. [108]
South Indian Indian Indian
Alagarasu et al. [109] Selvaraj et al. [136] Vidyarani et al. [80]
VDR VDR TNF ()238, )308) LTA_NcoI & Noc I intron TNFA )308 G A, )238 G A, )376 G A TNFA +488, )238, and )308 TNFA )308, G A )238 TNFA )308, G A )238
PTB PTB PTB No association PTB No association PTB No association PTB No association )238 polymorphism associated with pulmonary TB Association of TNF1 with TB
Indian Chinese South Indian South Indian Turkish Thai Iranian
Selvaraj et al. [61] Gao et al. [137] Selvaraj et al. [23] Selvaraj et al. [23] Ates et al. [21] Vejbaesya et al. [25] Amirzargar et al. [138]
Tumour necrosis factor
Columbia
Correa et al. [27, 139]

Table 3 Continued. Gene name Tumour necrosis factor Tumour necrosis factor Tumour necrosis factor Tumour necrosis factor Symbol TNFA )308 TNFA )308 TNFA )308 TNFA )308 Disease type PTB No association Lack of association with TB. Lack of association with TB. TNFA gene does not affect differential TB susceptibility. Susceptibility to TB Susceptibility to TB Population Chinese Colombian Indian Korean References Wu et al. [140] Henao et al. [126] Kumar et al. [141] Oh et al. [22]
TLR2 TLR2
Cathepsin Z
T597C Microsatellite polymorphisms in intron II CTSZ
Vietnam Koreans
Thuong et al. [96] Yim et al. [14, 97]
PTB
CD40 molecule, TNF receptor superfamily member 5 CD209 molecule (DC-SIGN)
CD40
PTB
CD209
PTB
The Gambia, Guinea-Bissau, Republic of Guinea, South Africa (Cape Town and Malawi) The Gambia, Guinea-Bissau, Republic of Guinea The Gambia, Guinea-Bissau, Republic of Guinea, South Africa (Cape Town and Malawi) South Africa (Cape Town), Tunisia
Cooke et al. [11]
Campbell et al. [142] Barreiro et al. [40, 143] Olesen et al. [144] Vannberg et al. [43] Barreiro et al. Ben-Ali et al. [143, 145] Buijtels et al. Thye et al. [146, 147] Fitness et al. [148] Stein et al. [149]
Chemokine (C-C motif) ligand 2 (Monocyte chemoattractant protein-1, MCP1) Chemokine (C-C motif) ligand 3 Chromosome regions: 1p31 (15 Mb from IL12RB2), 21q22 (containing IFNGR2); 2p22-2p16, 8p12-8q11, 8q21-8q23, 9p21-9q12, 11q14-11q23, 19p13-19q12, 22p13-22q11 (no candidate genes) Chromosome regions: 2q21-2q24, 5p13-5q22 (no candidate genes)
CCL2
PTB
Ghana, Zambia
CCL3
PTB TNF levels
South Africa (Malawi) Uganda
Chromosome region 8q12-q13 (gene not found) Chromosome 15q microsatellite markers Chromosome Xq microsatellite markers Complement component (3b 4b) receptor 1 (Knops blood group) C-type lectin domain family 4, member M (LSIGN)
PTB Resistance to infection PTB Chromosome 15q microsatellite markers Chromosome Xq microsatellite markers CR1 PTB
Uganda Morocco The Gambia, South Africa
Stein et al. [149] El Baghdadi et al. [150] Bellamy et al. [9]
PTB
The Gambia, South Africa
Bellamy et al. [9]
PTB
South Africa (Malawi)
Fitness et al. [148]
CLEC4M
PTB
South Africa (Cape Town)
Barreiro et al. [143]

Table 3 Continued. Gene name Cytotoxic T-lymphocyteassociated protein 4 Symbol Cytotoxic T-lymphocyteassociated protein 4 CTLA4 FUT2 GC (DBP)
T. Qidwai et al. ..................................................................................................................................................................
Disease type
Population
References
Fucosyltransferase 2 Group-specic component (vitamin D binding protein) Intercellular adhesion molecule 1 (CD54)
PTB PTB PTB
Ghana The Gambia South Africa (Xhosa, Cape Coloured)
Thye et al. [151] Bellamy et al. [117] Martineau et al. [152]
Interferon, gamma
Intercellular adhesion molecule 1 (CD54) ICAM1 IFNG
Fitness et al. [148]
PTB PTB, TB meningitis (TBM)
Interferon gamma receptor 1
IFNGR1
PTB, TNF levels
Interferon gamma receptor 2 Interleukin 1, alpha Interleukin 1, beta Interleukin 1 receptor antagonist Interleukin 8 Interleukin 12 receptor, beta-1 Lymphotoxin alpha Major histocompatibility complex Mannose-binding lectin (protein C) 2, soluble (opsonic defect) Melanocortin 3 receptor
IFNGR2
PTB PTB
IL1A IL1B IL1RN
PTB PTB PTB
South Africa (Malawi) The Gambia, Guinea-Bissau, Republic of Guinea, South Africa (Mixed) The Gambia, Guinea-Bissau, Republic of Guinea, Uganda The Gambia The Gambia, Guinea-Bissau, Republic of Guinea The Gambia The Gambia The Gambia
Rossouw et al. [55]
Cooke et al., Stein et al. [60, 169] Awomoyi et al. [153] Cooke et al. [60]
Bellamy et al. [53] Awomoyi et al. [154] Bellamy et al. [53]
IL8 IL12RB1 LTA HLA MBL2
PTB PTB PTB PTB PTB
The Gambia Morocco South Africa (Malawi) South Africa (Venda) The Gambia, South Africa (Malawi), Tanzania The Gambia, Guinea-Bissau, Republic of Guinea, South Africa (Cape Town and Malawi) South Africa (Cape Town) South African Guinea-Bissau Morocco
Cooke et al. [155] Remus et al. [156] Fitness et al. [148] Lombard et al. [157] Bellamy et al., Fitness et al., Soborg et al. [116, 117, 148] Cooke et al. [11]
MC3R
PTB
Nitric oxide synthase 2, inducible BTNL2 Pentraxin-related gene Protein tyrosine phosphathase, non-receptor type 22 (lymphoid) Purinergic receptor P2X, ligand-gated ion channel, 7 Solute carrier family 11, member 1
NOS2 rs2076530 SNP PTX3 PTPN22
PTB No signicant association with TB PTB PTB
Moller et al. [75] Moller et al. [46] Olesen et al. [144] Lamsyah et al. [106]
P2RX7
PTB
The Gambia
Li et al. [118]
SLC11A1
Clinical TB, IL10 production, PTB, TBM
The Gambia, Republic of Guinea, South Africa (Cape Town and Malawi), Tanzania
Awomoyi et al., Cervino et al., Fitness et al., Hoal et al., Soborg et al. [116, 148, 158160]

Table 3 Continued. Gene name Symbol Disease type PTB Population The Gambia, Morocco References Awomoyi et al., El Baghdadi et al. [150, 153, 161] Hoal et al. [160] Tosh et al. [164]
Solute carrier family 11, member 2 SP110 nuclear body protein Surfactant, pulmonary-associated protein A1 Surfactant, pulmonary-associated protein A2 Toll-interleukin 1 receptor (TIR) domain containing adaptor protein
SLC11A2 SP110
PTB, TBM PTB
South Africa (Cape Town) The Gambia, Guinea-Bissau, Republic of Guinea Ethiopia
SFTPA1
PTB
Malik et al. [163]
SFTPA2
PTB
Ethiopia
Malik et al. [163]
TIRAP
PTB, TBM
Toll-like receptor 2
TLR2
PTB PTB, TNF levels PTB
Algeria, The Gambia, Guinea-Bissau, Kenya, Republic of Guinea, South Africa (Mixed) Ghana Tunisia, Uganda Guinea-Bissau, South Africa (Malawi) Uganda The Gambia, Guinea-Bissau, South Africa (Malawi), Tanzania Guinea-Bissau South Africa (Malawi) Uganda
Dissanayeke et al., Khor et al. [111, 165]
Toll-like receptor 4
TLR4
PTB, TNF levels PTB, development of TB in HIV patients PTB PTB PTB, TNF levels
Toll-like receptor 9 Tumour necrosis factor Tumour necrosis factor receptor superfamily, member 1A Tumour necrosis factor receptor superfamily, member 1B Ubiquitin protein ligase E3A Vitamin D (1,25dihydroxyvitamin D3) receptor IFNG TLR 2
TLR9 TNF TNFRSF1A
Nejentsev et al. [166] Ben-Ali et al., Stein et al. [145, 149] Fitness et al., Olesen et al., Stein et al. [144, 148, 149] Stein et al. [149] Ferwerda et al., Fitness et al., Newport et al., Olesen et al. [144, 148, 167, 168] Olesen et al. [144] Fitness et al. [148] Stein et al. [169]
TNFRSF1B
PTB, TNF levels
Ghana, South Africa, Uganda The Gambia, Republic of Guinea, South Africa (KwaZulu-Natal) The Gambia, Guinea-Bissau, Republic of Guinea, South Africa (Venda) Croatian Caucasian Croatian Caucasian
Moller et al., Stein et al. [122, 169] Cervino et al. [159, 171]
UBE3A
PTB
VDR
PTB
T+874A and G+2109A TLR2-P631H
An association with disease severity Mutant might confer susceptibility to TB
Bellamy et al., Bornman et al., Lombard et al., Olesen et al. [79, 144, 157, 170] Etokebe et al. [63] Etokebe et al. [102]
have been detected in the present work (Tables 1 and 2). As DNA sequence variations modies transcriptional regulation, so it has been hypothesized that these probably alter the interaction of transcription factors to TFBS, leading to alteration in the level of gene product, and thus differential susceptibility to disease. Several candidate genes have been reported to be associated differentially in different ethnic background such as IL-10 1082 A G polymorphism was associated with TB in the Hong Kong Chinese [58], Colombian [126],
Spanish [56], Turkish [26] and Cambodian [127], but not in the Gambian and Spanish population (Table 3). In Korean populations it is not the IL-10 )1082A G polymorphism, but IL-10 )592 A C promoters polymorphism which has signicant association with TB [128]. This differential association arises as a result of potential inuence of pertinent environmental factors and genetic background in different populations. It is well-known that TB is partly under polygenic control. The genetic components that play role in host defence to TB encom-
T. Qidwai et al. ..................................................................................................................................................................
pass not only multiple alleles located on different genes and even on different chromosomes but also geneenvironment interaction. Variation in genotype frequencies between populations may contribute to inconsistent associations with disease development. Evolutionary selection also play role in development of disease. In response to disease pressure genome tries to selects those variations, which provide resistance against the disease. Malaria is an example of evolutionary selection, in which sickle cell anaemia is selected against the pressure of malaria in endemic region. There is an evidence of positive selection in early HIV-1 infection, which appears to be driven in many cases by escape from early cytotoxic T lymphocyte (CTL) responses via mutations in the APOBEC sequence, suggesting a role for APOBEC in determining the pathway of immune escape [129]. An opposite association of tuberculosis and autoimmune disease exists. This indicates that autoimmunity is selected against the pressure of tuberculosis as it provides resistance. Joint investigation of the genetic, immunologic and environmental factors and susceptibility to tuberculosis represents an innovative goal for obtaining a better understanding of the pathogenesis of the disease [130]. Understanding gained from knowledge of the effects of different alleles can contribute to the design of new therapeutic strategies including vaccines.
Contribution of promoter polymorphisms in expression divergence, evolution and tness
scription factors to regions of DNA in Drosophila melanogaster and Drosophila yakuba that have a common evolutionary origin; however, the relative afnity of these binding sites often differed between species. Evolutionary changes in the DNA sequence of cis-regulatory elements have altered the strength of the interaction between transcription factors and their binding sites without eliminating binding. In the light of these facts, we have concluded that TNF enhancer polymorphisms play important role in disease susceptibility resistance to diseases. We have also hypothesized that, those polymorphisms that lies in TFBS might play role in expression divergence, tness and evolution. This systematic review summarizes the associations between genetic polymorphisms and susceptibility to tuberculosis in different populations and in different genes. Inconsistencies observed between the included studies may be explained, at least in part, by differences between study populations. Our ndings support the hypothesis that presence of polymorphisms in TFBS of several genes altered the level of gene product. Alteration in the level of gene product play role as a risk factor during the development of TB and further studies are needed to clarify the potential underlying role of these SNPs.
Conclusion
We have analysed, different gene polymorphisms in tuberculosis casecontrol studies in different populations. The allele frequencies of gene vary from one population to other populations resulting in differential association with development of disease. Presence of polymorphisms affects the susceptibility to tuberculosis via altered expression level or structure of protein. Thus, host genes show genetic variability, and thus different response to this disease. In conclusion, this review summarises the associations between genetic polymorphisms and TB susceptibility and predicted polymorphisms in TFBS might play role in expression divergence, tness and evolution.
Natural selection has played some role in expression divergence, but the relative frequency of adaptive and neutral changes remains unclear [131]. Bradley et al. [132] observed differences in TFBS between species that were similar in regions of the genome. DNA sequence variation in TFBS, affects gene expression, gene expression to phenotypic variation and phenotypic variation to tness in the wild. The variations in the DNA region alter the interaction of TF and TFBS, thereby modulating the host parasite interaction. The genome tries to selects those variations which provide resistance against the disease. Malaria is an example of evolutionary selection, in which sickle cell anaemia is selected against the pressure of malaria in endemic region. The recruitment of different combinations of transcription factors to different genes allows expression of each gene to be regulated independently. Those changes that alter the activity or availability of transcription factors and the cis-regulatory sequences, to which they bind, can change gene expression. Both types of changes may result in evolution. The studies suggest that those changes that affect the cis-regulatory activity are the predominant source of expression divergence between species [131, 133, 134]. Bradley et al. [132] detected binding of the same tran-
Acknowledgment
The author is thankful to the University administration and Department of Biochemistry, Dr. R. M. L. Avadh University, Faizabad, for providing a supportive environment to carryout research activities.
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REVIEW doi: 10.1111/j.1365-3083.2012.02696.x ..................................................................................................................................................................

Scandinavian Journal of Immunology 2012 Blackwell Publishing Ltd.

T. Qidwai et al. DNA Sequence Variation and Regulation 569 ..................................................................................................................................................................

Tumour necrosis factor-alpha (TNF-a) polymorphisms

T. Qidwai et al. 570 DNA Sequence Variation and Regulation ..................................................................................................................................................................

SP110 and CARD15 polymorphisms

Scandinavian Journal of Immunology, 2012, 75, 568587

T. Qidwai et al. DNA Sequence Variation and Regulation 571 ..................................................................................................................................................................

T. Qidwai et al. 572 DNA Sequence Variation and Regulation ..................................................................................................................................................................

Interferon-c receptor-1(IFNcR1) polymorphisms

Vitamin D receptor (VDR) polymorphisms

Scandinavian Journal of Immunology, 2012, 75, 568587

T. Qidwai et al. DNA Sequence Variation and Regulation 573 ..................................................................................................................................................................

Natural resistance-associated macrophage protein (NRAMP1)

Vitamin D-binding protein (VDBP)

T. Qidwai et al. 574 DNA Sequence Variation and Regulation ..................................................................................................................................................................

The Toll-like receptors (TLR)

Toll-like receptor 4 polymorphism

Toll-like receptor 8 polymorphisms

Scandinavian Journal of Immunology, 2012, 75, 568587

T. Qidwai et al. DNA Sequence Variation and Regulation 575 ..................................................................................................................................................................

MIF, FCGR2A and FCGR3A gene polymorphisms

CCR2, MCP-1, SDF-1a & DC-SIGN gene polymorphisms

PTPN22 gene polymorphism

Human V-ATPase polymorphism

T. Qidwai et al. 576 DNA Sequence Variation and Regulation ..................................................................................................................................................................

TIRAP polymorphisms and susceptibility to childhood TB

Association analysis of susceptibility region on chromosome 5q31 for tuberculosis

Mannose-binding lectin polymorphisms

Genome-wide analysis of genetic susceptibility to tuberculosis

Complement receptor polymorphisms and Purinergic P2X7 receptor

Scandinavian Journal of Immunology, 2012, 75, 568587

T. Qidwai et al. DNA Sequence Variation and Regulation 577 ..................................................................................................................................................................

578 DNA Sequence Variation and Regulation

T. Qidwai et al. ..................................................................................................................................................................

Toll-like receptors, tumour necrosis factor-alpha, and interleukin-10 TLR2

Chen et al. [101]

Caucasian Mediterranean Russia Chinese Han population South African

FokI, TaqI, ApaI and BsmI

Africans, South Americans

Gao et al. [81]

PTPN22 Arachidonate 5-lipoxygenase ALOX5 BTNL2 MIF, FCGR2A, and FCGR3A

Moroccan Ghana, West Africa South African Moroccan

South Indian Indian Indian

Alagarasu et al. [109] Selvaraj et al. [136] Vidyarani et al. [80]

Indian Chinese South Indian South Indian Turkish Thai Iranian

Tumour necrosis factor

Correa et al. [27, 139]

Scandinavian Journal of Immunology, 2012, 75, 568587

T. Qidwai et al. DNA Sequence Variation and Regulation 579 ..................................................................................................................................................................

T597C Microsatellite polymorphisms in intron II CTSZ

Thuong et al. [96] Yim et al. [14, 97]

CD40 molecule, TNF receptor superfamily member 5 CD209 molecule (DC-SIGN)

Cooke et al. [11]

PTB TNF levels

South Africa (Malawi) Uganda

Uganda Morocco The Gambia, South Africa

Stein et al. [149] El Baghdadi et al. [150] Bellamy et al. [9]

The Gambia, South Africa

Bellamy et al. [9]

South Africa (Malawi)

Fitness et al. [148]

South Africa (Cape Town)