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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
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.
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
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,
2012 The Authors. Scandinavian Journal of Immunology 2012 Blackwell Publishing Ltd.
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.
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.
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].
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.
(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.
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.
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].
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
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]
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
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
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]
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
Lamsyah et al. [106] Herb et al. [34] Moller et al. [46] Sadki et al. [108]
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
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]
Columbia
TLR2 TLR2
Cathepsin Z
Vietnam Koreans
PTB
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
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
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
PTB
PTB
CLEC4M
PTB
2012 The Authors. Scandinavian Journal of Immunology 2012 Blackwell Publishing Ltd.
Disease type
Population
References
Fucosyltransferase 2 Group-specic component (vitamin D binding protein) Intercellular adhesion molecule 1 (CD54)
Interferon, gamma
IFNGR1
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
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
Cooke et al., Stein et al. [60, 169] Awomoyi et al. [153] Cooke et al. [60]
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
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
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]
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
South Africa (Cape Town) The Gambia, Guinea-Bissau, Republic of Guinea Ethiopia
SFTPA1
PTB
SFTPA2
PTB
Ethiopia
TIRAP
PTB, TBM
Toll-like receptor 2
TLR2
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
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
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
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
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],
2012 The Authors. Scandinavian Journal of Immunology 2012 Blackwell Publishing Ltd.
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-
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.
References
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