REVIEW doi: 10.1111/j.1365-3083.2012.02696.

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DNA Sequence Variation and Regulation of Genes

Involved in Pathogenesis of Pulmonary Tuberculosis
T. Qidwai*, F. Jamal* & M. Y. Khan 

*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, Faizabad-
224001, U.P., India. E-mails: farrukhrmlau@
gmail.com; journal.farrukh@gmail.com
Abstract
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
identified that appear to be important in tuberculosis. In this article, several
case–control 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 modification of
transcriptional regulation of gene.

DNA sequence variation in both parasite and host

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 world’s 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 tubercu-
losis, including multi-drug (MDRTB) and extensively
drug resistant TB (XDRTB), it is becoming increasingly
difficult to treat and control disease in developing
countries [5].
have been known to play an important role in susceptibil-
ity to disease, and consequently an improve understand-
ing of the host response to Mtb will facilitate the
development of new vaccines and therapeutics [6]. A
number of genes have been identified 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 [8–13]. The host genetic factors and susceptibility to
tuberculosis has been extensively explored in various eth-
nic populations. Some important candidate genes like
human leucocyte antigen ⁄ alleles and non-human leuco-
cyte antigen genes, such as cytokines and their receptors,
chemokines and their receptors, pattern recognition recep-
tors, solute carrier family 11A member 1, (natural resis-
tance-associated macrophage protein 1) and purinergic
P2X7 receptor gene polymorphisms, reflects differential

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568 Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
T. Qidwai et al. DNA Sequence Variation and Regulation 569
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association with susceptibility to TB in different popula- Table 1 List of SNPs found in the 5¢ upstream region extending from
tion [14]. This article presents some important host )3000 to +500 BP with respect to TSS in the gene involved in the
tuberculosis pathogenesis (IFNGR1, IL-1B, IL1R1, ALOX 5, CARD
genetic polymorphisms in genes involved in host immune 15, CD 209, Frizzled homolog 5 Drosophila (FZD5), IL-18, Interlukin
response and their role in susceptibility ⁄ resistance to 12 receptor beta 2, Lymphotoxin alpha (LTA), Lymphotoxin beta
pulmonary tuberculosis (PTB). Furthermore, this review (LTB), PTPN 22, SP110, TLR 4, TLR2, WNT5A, TNF, VDR,
covers several published case–control studies including NOS2A). Bold SNPs are experimently validated.
different genes and genome wide linkage in different
rs10004467 rs11679983 rs2234650 rs3917346 rs5833468
population. Moreover, we have predicted 275 single rs10116253 rs11707296 rs2234652 rs3917347 rs5833469
nucleotide polymorphisms (SNPs) in transcription factor rs10168222 rs11710229 rs2239704 rs4141631 rs5833469
binding of 19 genes involved in pathogenesis of tubercu- rs10187268 rs11805450 rs2307151 rs4141632 rs5875327
losis. The experimentally validated SNPs are highlighted rs10408865 rs12024929 rs2314814 rs4141633 rs589557
in Table 1. All these SNPs are reported in db SNP data- rs10409294 rs12142823 rs2405433 rs4248157 rs5900307
base, and only those have been predicted that fall in the rs1041981 rs12142823 rs2471961 rs4248158 rs590386
rs10459953 rs12199078 rs2488457 rs4248159 rs6478317
region of transcription factor binding sites (TFBS). rs1047898 rs12264166 rs2507961 rs4248160 rs6593482
rs10553050 rs12351464 rs2515924 rs4248161 rs6708048
rs10560589 rs12356668 rs2516312 rs4248162 rs6710598
Tumour necrosis factor-alpha (TNF-a)
rs10560590 rs12356668 rs2649867 rs4248163 rs6743326
polymorphisms rs10601145 rs12359811 rs2649868 rs4248164 rs6743330
Although the involvement of host genetic factor(s) is cru- rs10664363 rs12378184 rs2682448 rs4516035 rs6743338
rs10759931 rs12497254 rs2682449 rs4645834 rs6758647
cial; several host immune response genes are also engaged
rs10759932 rs12525508 rs2708920 rs4645836 rs6761218
in determining susceptibility towards developing the rs10875696 rs12720460 rs2708921 rs4645838 rs6761220
active form of tuberculosis [15, 16]. TNF-a and lympho- rs10983755 rs12720460 rs2736195 rs4645839 rs6761237
toxin-a (LT-a) genes located within the MHC III region rs11102689 rs12720463 rs2736196 rs4647173 rs6761245
of chromosome 6 not only shows close linkage to the rs11168296 rs12762303 rs2737193 rs4647174 rs6761335
HLA class I (HLA-B) and class II (HLA-DR) genes but rs11209045 rs12812972 rs2737194 rs4647175 rs6761336
are also involved in the pathogenesis of tuberculosis due rs11214105 rs1293344 rs2779249 rs4647176 rs6831031
rs11239494 rs1327473 rs2779249 rs4647178 rs7139166
to its role in the formation and maintenance of granulo- rs11297581 rs1327474 rs2779249 rs4647179 rs735239
mas [17]. Moreover, it also plays a major role in host rs11329294 rs13374580 rs2779250 rs4647180 rs735240
defence to Mtb by its synergistic action with interferon-c rs11329295 rs13426951 rs2844482 rs4647181 rs7359874
(IFN-c) to activate macrophages and thereby affects dis- rs11329306 rs16826884 rs2857706 rs4647189 rs736160
ease perpetuation [18]. Elevated serum TNF-a (sTNF-a) rs11343699 rs16944 rs2857711 rs4647191 rs7381804
levels have been reported in advanced tuberculosis rs11395090 rs17109841 rs2857712 rs4647194 rs7548827
rs11433379 rs17129717 rs2857713 rs4647195 rs7556811
patients compared with those with mild tuberculosis and
rs1143623 rs17129718 rs2857713 rs4647198 rs7556903
healthy controls. Several promoter polymorphisms of rs1143624 rs17129719 rs2871448 rs4785224 rs760363
TNF-a and intron 1 polymorphism of LT-a have been rs1143627 rs17129722 rs2904614 rs4804804 rs7758790
associated with altered levels of TNF-a [19, 20]. Some of rs1143628 rs17129726 rs3018465 rs4987086 rs7765227
these polymorphisms have been reported in several ethnic rs11465355 rs17129728 rs3087258 rs4987105 rs7766988
groups [21–26]. Correa et al. [27] detected TNF-a gene rs11465357 rs17129733 rs3093540 rs4987106 rs7866214
polymorphisms ()308 and )238) in controls and patients rs11465360 rs1799765 rs3093541 rs5021469 rs7913948
rs11465362 rs1799916 rs3093544 rs5743259 rs8046608
of several diseases (systemic lupus erythematosus (SLE), rs11465363 rs1800195 rs3093546 rs5743262 rs8111321
rheumatoid arthritis (RA), primary Sjogren’s syndrome rs11465364 rs1800610 rs3093547 rs5743263 rs8112852
(SS) and tuberculosis. TNF -308G was associated with rs11465365 rs1800630 rs3093548 rs5743264 rs893629
TB whereas )308 GG genotype was protective for au- rs11465366 rs1800683 rs3093549 rs5743266 rs893630
toimmunity. TNF-238A allele was protective for autoim- rs11465367 rs1800919 rs3093550 rs5743266 rs909253
munity, but acted as a susceptibility factor for TB. rs11465368 rs181720 rs3093551 rs5743267 rs915654
rs11536861 rs187238 rs3093562 rs5744223 rs9267499
Haplotype -308A-238G have been reported as a protec-
rs11544762 rs1896260 rs3093563 rs5744224 rs9267500
tive factor for TB, but susceptibility factor for RA, SLE rs11574002 rs1927914 rs3093661 rs5744225 rs9267501
and primary SS. Opposite association of TNF polymor- rs11574003 rs1946518 rs3179060 rs5744226 rs9279357
phism with autoimmunity and TB, suggests that autoim- rs11574004 rs1946519 rs360719 rs5744227 rs9279358
mune diseases are a consequence of natural selection for rs11574005 rs2009658 rs3762315 rs5744229 rs9281526
enhanced TB resistance. Ates et al. [21] identified TNF-a rs11574008 rs2066850 rs3762316 rs5833463 rs9282875
()308 G ⁄ A, )238 G ⁄ A, )376 G ⁄ A) and IL10 ()1082 rs11574009 rs2071590 rs3762317 rs5833464 rs9380263
rs11574012 rs2076752 rs3789612 rs5833465 rs956730
G ⁄ A, )819 C ⁄ T, )592 C ⁄ A) polymorphisms in patients rs11575936 rs2099683 rs3834764 rs5833466 rs9890573
with TB and healthy controls. A significant association rs11576006 rs2228088 rs3917345 rs5833467 rs9895793
was found between TB and )1082 G allele.

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Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
570 DNA Sequence Variation and Regulation
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Significant difference was observed in IL10 GCC and
ACC haplotypes distribution between TB cases and con-
trols. No significant 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] per-
formed a case–control study including TNF-a gene
()1031, )863, )857, )308, )238) and LT-a gene
(+252) polymorphisms in North-Indian population. No
significant differences of the allele frequencies between
the tuberculosis patients and controls were reported. All
the polymorphisms included in their study did not give
a significant association with any of the patient sub-
groups; but observed a significant 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 inflammatory disease as well as in the regu-
lation 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-inflammatory 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 case–con-
trol 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 associ-
ation was strongest with TB for the ‘non-5 ⁄ 760A’ haplo-
type as compared to ‘non-5 ⁄ 760G’ haplotype.
CD209 polymorphism
CD209 on chromosome 19p13.3 encodes Dendritic Cell-
Specific 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-lympho-
cytes 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
T. Qidwai et al.
Calmette–Gue´rin (BCG), Helicobacter pylori, Klebsiella pneu-
moniae, Streptococcus pneumoniae, HIV-1, HIV-2, SIV-1,
Dengue virus, Ebola Virus, Cytomegalovirus, Hepatitis C
virus, Schistosoma mansoni, Leishmania pifanoi and Candida
albicans [36–39]. The contribution of CD209 polymor-
phisms 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 infec-
tious disease susceptibility or protection in M. leprae.
Martin et al. [42] demonstrated the )336G allele associa-
tion 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 poly-
morphism and susceptibility to tuberculosis in sub-
Saharan Africans. Significant protection was observed
with CD209 )336G variant allele in individuals from
sub-Saharan Africa and cases with )336GG were signifi-
cantly 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 iso-
lated case, an association with TB susceptibility. Eight
SP110 polymorphisms including two novel polymorphisms
in a South African population, revealed no significant asso-
ciation 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 oligo-
merization domain 2 (NOD2) proteins and are considered
as susceptibility gene for Crohn’s disease (CD). As a can-
didate 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
find statistically significant 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 susceptibil-
ity gene for TB in the South African Coloured.
BTNL2 polymorphisms
Butyrophilin-like2 gene (BTNL2) gene, a MHC class II
gene-linked butyrophilin family member has recently
Scandinavian Journal of Immunology, 2012, 75, 568–587
T. Qidwai et al.
..................................................................................................................................................................
been associated with diseases, such as tuberculosis, sar-
coidosis and leprosy. As a candidate gene for tuberculosis
in the South African Coloured population, 18 SNPs geno-
typed in BTNL2 gene in cases with PTB failed to estab-
lish a significant 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 hapl-
otypes 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 stratified, South African population
resembles the African-Americans more than white popula-
tions. Six SNPs of BTNL2 gene in tuberculosis cases in
Chinese Han population did not reflect any significant
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 significant association between the rs3763313,
rs9268494, rs9268492 SNPs in the BTNL2 gene and
tuberculosis. Haplotypes 1–5, 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 significant
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 cyto-
kine, during M. tuberculosis infection and genes involved
in the regulation of inflammatory cytokine, interferon
gamma may influence 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 polymor-
phism was previously associated with protection against
pulmonary TB in south Indian, Russian, but not in
Gambian populations [51–53]. 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 heterozy-
gosity and homozygosity for the IL1B )511-C allele. No
association existed between the IL1B+3953-T ⁄ C poly-
morphism 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.
DNA Sequence Variation and Regulation 571
healthy Gambian individuals who were homozygous for
IL1B )511-T allele failed to exhibit a significant increase
in IL-1b production in response to LPS after IFN-c
priming.
IFN-c plays a central role in the modulation of tuber-
culosis 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 first intron is associated with a high level of in vitro
cytokine production [54]. In a recent study, polymor-
phism at position +874 is associated with risk of tuber-
culosis in different population [55, 56]. Ansari et al. [4]
found that the ratio of two key cytokines (IFN-c and
IL10) exhibited significant correlation with the severity
spectrum of tuberculosis in Pakistani population. Fur-
thermore, 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 findings are consistent with the role of
IL10 in reducing collateral tissue damage and the protec-
tive 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 Sicil-
ians, South Africans, Hong Kong Chinese and Spanish,
[57–61] 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 inde-
pendently predictive of a lower likelihood of sputum con-
version. 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 significantly 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-inflammatory cytokine
produced by monocytes, macrophages, DCs and B lym-
phocytes. SNP in the gene responsible to express this
subunit was first described by Hall et al. [64]. Several
polymorphisms in promoter, introns and 3¢UTR in the
IL-12B gene are associated with TB in various popula-
tions, 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 polymor-
phism 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
572 DNA Sequence Variation and Regulation
..................................................................................................................................................................
G378R) and one synonymous substitution in the extra-
cellular 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 significantly
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 myco-
bacterial 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 sig-
nificantly different. In studies where SNP affect transcrip-
tion, the expression of IFNcR1 gene does not confer
susceptibility to disease in patients from Croatia [65]. A
significant association exists between the protective
(CA)n polymorphism (22 repeats, 192 FA1), located in
intron five of the IFNcR1 gene and GT promoter haplo-
type ()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
G·2109A), 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 myco-
bacterial disease have also been explored that has muta-
tions in one of two subunits of the IFN-c receptor gene
(IFN cR1 and IFN cR2) [66]. The polymorphisms identi-
fied in Gambians were at +95, )56 and )270 nucleo-
tides 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 pro-
duced by tuberculosis-infected human macrophages and
by epithelial cells is anti mycobacterial against M. tubercu-
losis [67]. The alveolar macrophages from the lungs of
patients with tuberculosis express NOS2A in potentially
T. Qidwai et al.
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
case–control 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 trans-
ducer and activator of transcription protein 1, and NF-
jB repressing factor [71]. The )954G ⁄ C variant was
originated as a consequence of selective pressure of Plas-
modium 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 popula-
tion [75]. Haplotype of two functional (rs9282799 and
rs8078340) SNPs in the NOS2A promoter have been
significantly associated with tuberculosis. Presence of T
allele decreases the DNA-protein complex formation and
the duration of DNA–protein 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 case–control 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 gene–gene interac-
tions were between NOS2A rs2248814 and IFNGR1
rs1327474 and NOS2A rs944722 and IFNGR1 rs1327474.
Three other SNPs in NOS2A interacted with TLR4
rs5030729 and five other NOS2A SNPs interacted with
IFNGR1 rs1327474. Interestingly, no significant associa-
tions existed in Caucasians. These results suggested that
NOS2A variants may contribute to TB susceptibility, par-
ticularly 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
Scandinavian Journal of Immunology, 2012, 75, 568–587
T. Qidwai et al.
..................................................................................................................................................................
susceptibility to M. tuberculosis infection [77]. Polymor-
phisms 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 influence
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 filtrate antigen
(CFA) of Mtb [80]. The ApaI aa genotype and bbaaTT
extended genotype were associated with a significantly
decreased percentage of granzyme A positive cells in
normal healthy controls. The study suggests that 1,
25(OH)2D3 suppresses granzyme A probably by down-
regulating Th1 cytokine response. Gao et al. [81] has
reviewed VDR polymorphisms and TB susceptibility and
quantitatively summarized associations of the polymor-
phisms (FokI, TaqI, ApaI and BsmI). Among Asians, the
FokI ff genotype showed a pronounced positive associa-
tion; a significant inverse association was observed for the
BsmI bb genotype and for TaqI and ApaI polymorphisms
associations were marginal. None of the polymorphisms
studied showed significant association to TB among Afri-
cans or South Americans.
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. Combi-
nation 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 cir-
culating 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 phe-
notype was seen among patients and the control group.
 2012 The Authors.
Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
DNA Sequence Variation and Regulation 573
Also, the frequency of Gc2 in tuberculosis patients was
slightly, but not significantly 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 pop-
ulation. A total of 1067cases and 1084controls in eight
publications were included in the study; all genotype fre-
quencies were consistent with Hardy–Weinberg equilib-
rium. 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: 1.31–2.16, P < 0.001), 1.78 (95% CI:
1.38–2.30, P < 0.001), 1.56 (95% CI: 0.72–3.35,
P = 0.26), respectively when compared with their corre-
sponding common homozygotes. The cumulative sum-
mary 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 3¢UTR 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 tuber-
culosis, 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, 3¢UTR 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 statisti-
cally significant differences were observed in allele fre-
quencies of INT4, D543, 3¢UTR 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% (0.07–0.67 (P = 0.001)] and )308
A variant in TNF-alpha promoter region [ORs: 0.26 CI:
95% (0.07–0.77) (P = 0.006)] were significantly more in
PTB patients than healthy controls.
Natural resistance associated macrophage protein1
(Nramp1 ⁄ Slc11a1) gene has been associated with myco-
bacterium infection [88]. To determine the association of
Nramp1 ⁄ Slc11a1 with tuberculosis and leprosy, analysis
was performed using restriction fragment length poly-
morphisms of three variants (D543N, 3¢UTR 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
574 DNA Sequence Variation and Regulation
..................................................................................................................................................................
with paucibacillary type of leprosy (P = 0.032, 1 df,
OR = 2.975, CI = 1.057–8.373), but not to multibacil-
lary type (P = 0.173, 1 df, OR = 2.248, CI = 0.682–
7.404) have been observed. No significant 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 host–pathogen 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-deficient 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 mac-
rophages, 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 cyto-
solic part of this receptor, out of which, only two have
been linked to reducing NF-jB activation and increasing
the risk of infection. The first 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 specific 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 sub-
stitutes 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 heterodi-
mer binding sites to mycobacterial lipopeptide, as indi-
viduals 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 guan-
ine-thymine (GT) microsatellite repeat polymorphism
T. Qidwai et al.
(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 (mi-
crosatellite 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 pul-
monary TB. As opposed to TB patients without systemic
symptoms, lower )196 to )174 deletion ⁄ deletion geno-
type frequency existed in patients with systemic symp-
toms 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 pleu-
ritis 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 car-
rying the T allele. The patients of TB carrying homozy-
gous 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 specific TLR2 hap-
lotype 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 domi-
nant 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
findings reflect that TLR2-P631H allele could be associ-
ated 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] anal-
ysed the association between TLR4 Asp299Gly and
Thr399Ile SNPs and active TB, in Caucasian Mediterra-
nean HIV-infected individuals. Asp299Gly were indepen-
dently 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
Scandinavian Journal of Immunology, 2012, 75, 568–587
T. Qidwai et al.
..................................................................................................................................................................
gene, four polymorphisms on chromosome X showed evi-
dence 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 evi-
dence 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 significantly associated
with lower risk of PTB, in comparison with other geno-
types. 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 signifi-
cant association exists for TLRs and IL-10 gene polymor-
phisms and tuberculosis.
PTPN22 gene polymorphism
PTPN22 gene encodes the lymphoid tyrosine phospha-
tase 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 popula-
tion. A study of two missense polymorphisms of the
PTPN22 gene (R620W and R263Q) and susceptibility
to TB in the Moroccan population revealed a statistically
significant 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 vari-
ants 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.
 2012 The Authors.
Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
DNA Sequence Variation and Regulation 575
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 popula-
tion [106]. The genotyping for MIF-173 (G ⁄ C) (rs755622),
FCGR2A-131 H ⁄ R (rs1801274) and FCGR3A-158V ⁄ F
(rs396991) revealed a statistically significant 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 FCGR3A-
158V ⁄ F polymorphisms and tuberculosis disease. These
finding indicates that MIF )173*C variant may play
an important role in the development of active tubercu-
losis.
CCR2, MCP-1, SDF-1a & DC-SIGN gene
polymorphisms
Chemokine, chemokine receptor and DC-SIGN gene
polymorphisms were associated with susceptibility ⁄ resis-
tance to HIV and HIV-TB in south India [109]. CCR2
V64I (G ⁄ A), monocyte chemoattractant protein-1 (MCP-
1) )2518 A ⁄ G, stromal cell derived factor-1alpha; (SDF-
1alpha) 3¢UTR 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 signifi-
cant differences in genotype frequencies of CCR2 V64I,
MCP-1 )2518 and DC-SIGN polymorphisms were
observed between the study groups. Significantly
increased frequency of GG genotype of SDF-1alpha poly-
morphism was observed among positive for HIV and
PTB patients compared with healthy controls. The GG
genotype of SDF-1alpha 3¢UTR 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 com-
pared 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-A2-
DRB1*1502 haplotype might be associated with suscep-
tibility 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].
576 DNA Sequence Variation and Regulation
..................................................................................................................................................................
TIRAP polymorphisms and susceptibility to
childhood TB
The adaptor protein TIRAP mediates downstream signal-
ling 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] identified 13 SNPs, and found significant dif-
ferences in frequency of the variants between the two eth-
nic groups. The frequency of individual polymorphisms
or combinations did not vary between TB cases and con-
trols in either cohort. The 558C fi 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.
Mannose-binding lectin polymorphisms
Mannose-binding lectin (MBL) is considered as an impor-
tant component of innate immunity. Four functional
MBL2 alterations in codons 52, 54, 57 and in the pro-
moter at position c.1-290 are correlated with significantly
lower MBL serum levels. These variants have been associ-
ated 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 des-
ignated 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 deficiency is an example of evolution-
ary selection, as MBL deficiency 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 hetrozyg-
otes for MBL54 have protection against tuberculosis
meningitis [113]. TB patients as compared with controls
have an increased genotype frequencies for mutant homo-
zygotes 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].
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. Homo-
zygotes, one in five of CR1polymorphisms (Q1022H) are
T. Qidwai et al.
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 pulmo-
nary TB in Gambia [118]. Southeast Asian refugees in
Australia had no association of the 1513 SNP with pul-
monary 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 5q23.2–31.3 has
been identified 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-five SNPs
located within candidate genes covering SLC22A4, SLC22A5,
IRF1, IL5, RAD50, IL13, IL4, KIF3A and SEPT8 were
genotyped. Analysis revealed that the most significant
association with tuberculosis in haplotypes comprising
SNPs rs274559, rs274554, and rs274553 of SLC22A5
gene, which remained significant after multiple testing
corrections. The two haplotypes within the SLC22A4 and
KIF3A region were associated with tuberculosis. Haplo-
types of SLC22A5 were significantly associated with the
expression levels of RAD50 and IL13. The variants car-
ried by the haplotypes of SLC22A4, SLC22A5 and
KIF3A region potentially contribute to tuberculosis
susceptibility among the Thai population.
Genome-wide analysis of genetic susceptibility to
tuberculosis
Bellamy et al. [9] performed genome-wide analysis of
genetic susceptibility to tuberculosis in Africans. A two-
stage genome-wide linkage study was performed to search
for regions of the human genome containing tuberculo-
sis-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-suscepti-
bility gene, 22 markers from these regions were geno-
typed 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 identification of major
genes for multifactorial infectious diseases of humans.
Thye et al. [120] identified a genetic variant, which
increases susceptibility to tuberculosis (TB) in African
Scandinavian Journal of Immunology, 2012, 75, 568–587
T. Qidwai et al. DNA Sequence Variation and Regulation 577
..................................................................................................................................................................

populations. These studies involved analysing hundreds Table 2 List of transcription factors, which have transcription factor
of thousands of genetic markers across the human ge- 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
nomes in search of variants found in patients, but not in 15, CD 209, Frizzled homolog 5 Drosophila (FZD5), IL-18, Interlukin
healthy controls. 12 receptor beta 2, Lymphotoxin alpha (LTA), Lymphotoxin beta
(LTB), PTPN 22, SP110, TLR 4, TLR2, WNT5A, TNF, VDR,
NOS2A.
Polymorphism of 3¢UTR region of TNFR2 coding
gene and its role in clinical tuberculosis AGL3 Dorsal_1 IL12RB2 RREB-1
AML-1 Dorsal_2 Irf-1 SAP-1
TNFR2 encoded by the TNFRSF1B gene is one of the ARNT E2F Max Snail
important TNF-a receptors; its polymorphisms were ear- Athb-1 E4BP4 MEF2 SOX17
lier suggested as potential markers of host susceptibility ATHB5 E74A Myc-Max Sox-5
Brachyury Evi-1 Myf Spz1
to TB. Three SNPs in TNFRSF1B 3¢UTR (rs1061624,
Broad-complex_1 FREAC-4 NF-kappaB SQUA
rs5030792, rs3397) was performed in Han Chinese Broad-complex_4 Hen-1 NF-Y Staf
paediatric population (229 TB patients and 233 control bZIP910 HFH-2 n-MYC SU_h
subjects). The rs5030792 was found homozygous CF2-II HFH-3 NRF-2 Tal1beta-E47S
(TT genotype) in all individuals [121]. The rs3397-T CFI-USP HLF p65 TBP
Chop-cEBP HMG-IY Pax-4 TEF-1
allele was almost equally represented in both gender
COUP-TF HNF-1 Pax6 Thing1-E47
groups in this study; in particular, it was detected in CREB HNF-3beta Pbx USF
33.9% and 35.2% in female cases and controls, respec- c-REL Hunchback RORalfa-1
tively (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, respec- satellite repeats (SSR) and SNP. Among them, SNPs is
tively (P = 0.007) [122]. In contrast, rs1061624-A allele, the most common type of variations. Presence of SNPs in
acting recessively, was a possible risk factor for clinical coding region affects protein structure while the pro-
TB in females (P = 0.03). The rs1061624 heterozygotes moter region affects its level. Alteration in level or struc-
were overdominant in controls versus patients (P = ture caused by DNA sequence variations have been
0.015) that warrants further study of their hypothetical shown to play a crucial role in development of active
advantage in TB. Neither of the common haplotypes was form of disease. Several host genes have been shown to
associated with susceptibility to TB. contribute significantly towards development of active
tuberculosis [124]. As only a small percentage of infected
individuals develop active form of disease, the difference
Methods
in polymorphisms within genes involved in host immune
In Silico detection of DNA sequence variations modifying response has been proposed as a possible reason to explain
transcriptional regulation. DNA sequence variations (poly- this phenomenon [104].
morphisms) affecting the expression levels of genes play Although several mechanisms operate in gene regula-
important roles in the pathogenesis of diseases. We have tion, transcriptional control seems to be crucial. Promoter
identified several polymorphisms affecting the regulation hypermethylation and presence of polymorphisms in reg-
of genes with the help of a web tool called regulatory ulatory region are the two most important factors that
analysis of variation in enhancers (RAVEN). This web interfere with the gene regulation and our hypothesis is
tool is available at http://www.cisreg.ca. On entering the that during disease conditions, there is up regulation or
keywords, search engine gives a list of human gene. Click down regulation of gene (transcriptional dysregulation).
the gene of interest, genome location of gene is displayed In this context the infection of Plasmodium falciparum
by the software. Selection of the genomic regions from upregulates the expression of TNF-alpha which in turn
)3000 to 500 bp gives results in graphical and in tabu- increases the expression of adhesion molecules on the sur-
lated forms. In the result view, we have option for analysis face of blood vessels. Under conditions of certain cancers,
of SNPs with a particular transcription factor or the entire there is down regulation of genes. GSTP1 expression is
transcription factor. JASPAR: an open-access database for markedly decreased in various adenocarcinoma and pros-
eukaryotic transcription factor binding profiles. This soft- tatic intraepithelial neoplasia (PIN) specimens [125].
ware was developed by Andersen et al. [123] and results Promoter polymorphisms in TFBS (cis-elements)is an
are shown in Tables 1 and 2. important factor that contributes to dysregulation of
genes and thus plays a role in pathogenesis of tuberculo-
sis. Promoter methylation interferes with gene expression
Discussion
as methyl group disrupts the interaction between tran-
In human genome, different types of variations are scription factors and TFBS. Several polymorphisms in
reported such as copy number variations (CNV), micro- TFBS of genes involved in pathogenesis of tuberculosis

 2012 The Authors.

Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
578 DNA Sequence Variation and Regulation
..................................................................................................................................................................
Table 3 Overview of various case–control studies including different genes in different populations of the word up to 2010.
Gene name
Tumour necrosis factor
TLR4
Toll-like receptors,
tumour necrosis
factor-alpha, and
interleukin-10
TLR2
TLR4
TLR8
BTNL2
IL4, IL10, IL12B,
IL12RB, IL12RB2,
IL18, WNT5A, FZD5
TLRs, TNF-a and IL-10
FokI, TaqI, ApaI
and BsmI
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
Tumour necrosis factor
T. Qidwai et al.
Symbol Disease type Population References
LTA_NcoI; TNFA )238, Lack of association with TB. North Indian Sharma et al. [20]
)308, )857, )863, )1031
Asp299Gly SNP Independent association Caucasian Ildefonso et al. [103]
Mediterranean
HIV-infected
patients
1805 G ⁄ T TLR1, 2258 A ⁄ G TNF-a associated with TB, China Ma et al. [105]
TLR2, )857 C ⁄ T, and )863 no association of TLRs and
A ⁄ C TNF-a IL-10 TB
)100 (microsatellite repeats), TLR2 variants play a role in China Chen et al. [101]
)16934 (T>A), )15607 the development of TB
(A>G), )196 to )174
insertion>deletion), and
1350 (T>C)
TLR4 Asp299Gly and Association with TB Caucasian Ildefonso et al. [103]
Thr399Ile Mediterranean
rs3764880 (Met1Val) Association with TB Russia Davila et al. [104]
rs2076530 Association with TB Chinese Han Lian et al. [47]
population
IL 12 B haplotypes A nominally significant South African Moller et al. [45]
association
1805 G ⁄ T in TLR1, 2258 Variants in TNF-a associated Chinese Ma et al. [105]
A ⁄ G in TLR2, )857 C ⁄ T, with susceptibility to PTB.
TNF-a )863 & A ⁄ C, )819 no significance with TLRs
C ⁄ T IL-10 and IL-10 variants
FokI ff genotype show positive Africans, Gao et al. [81]
association with TB & South Americans
inverse association with BsmI
bb genotype
R263Q (G788A), R620W Affect susceptibility to TB Moroccan Lamsyah et al. [106]
(C1858T)
760G>A exonic, &a VNTR Association with TB Ghana, Herb et al. [34]
in promoter West Africa
rs2076530 No association with TB South African Moller et al. [46]
MIF-173 (G ⁄ C) (rs755622), No association Moroccan Sadki et al. [108]
FCGR2A-131 H ⁄ R withFCGR2A-131H ⁄ R and
(rs1801274), and FCGR3A-158V ⁄ F variants
FCGR3A-158V ⁄ F while MIF )173*C variant
(rs396991) play role in active TB
VDR HIV-TB South Indian Alagarasu
et al. [109]
VDR PTB Indian Selvaraj et al. [136]
VDR PTB Indian Vidyarani et al. [80]
VDR PTB Indian Selvaraj et al. [61]
VDR PTB Chinese Gao et al. [137]
TNF ()238, )308) PTB No association South Indian Selvaraj et al. [23]
LTA_NcoI & Noc I intron PTB No association South Indian Selvaraj et al. [23]
TNFA )308 G ⁄ A, PTB No association Turkish Ates et al. [21]
)238 G ⁄ A, )376 G ⁄ A
TNFA +488, )238, and PTB No association Thai Vejbaesya et al. [25]
)308
TNFA )308, G ⁄ A )238 )238 polymorphism Iranian Amirzargar et al. [138]
associated with pulmonary
TB
TNFA )308, G ⁄ A )238 Association of TNF1 with TB Columbia Correa et al. [27, 139]
Scandinavian Journal of Immunology, 2012, 75, 568–587
T. Qidwai et al. DNA Sequence Variation and Regulation 579
..................................................................................................................................................................

Table 3 Continued.

Gene name Symbol Disease type Population References

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

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Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
580 DNA Sequence Variation and Regulation T. Qidwai et al.
..................................................................................................................................................................

Table 3 Continued.

Gene name Symbol Disease type Population References

Cytotoxic Cytotoxic
T-lymphocyte- T-lymphocyte-
associated protein 4 associated
protein 4
CTLA4 PTB Ghana Thye et al. [151]
Fucosyltransferase 2 FUT2 PTB The Gambia Bellamy et al. [117]
Group-specific component GC (DBP) PTB South Africa (Xhosa, Cape Martineau et al. [152]
(vitamin D binding Coloured)
protein)
Intercellular adhesion Intercellular Fitness et al. [148]
molecule 1 (CD54) adhesion
molecule 1
(CD54)
ICAM1 PTB South Africa (Malawi)
Interferon, gamma IFNG PTB, TB meningitis The Gambia, Rossouw et al. [55]
(TBM) Guinea-Bissau, Republic
of Guinea, South Africa
(Mixed)
Interferon gamma IFNGR1 PTB, TNF levels The Gambia, Cooke et al., Stein
receptor 1 Guinea-Bissau, Republic et al. [60, 169]
of Guinea, Uganda
PTB The Gambia Awomoyi et al. [153]
Interferon gamma IFNGR2 PTB The Gambia, Cooke et al. [60]
receptor 2 Guinea-Bissau, Republic
of Guinea
Interleukin 1, alpha IL1A PTB The Gambia Bellamy et al. [53]
Interleukin 1, beta IL1B PTB The Gambia Awomoyi et al. [154]
Interleukin 1 IL1RN PTB The Gambia Bellamy et al. [53]
receptor antagonist

Interleukin 8 IL8 PTB The Gambia Cooke et al. [155]

Interleukin 12 IL12RB1 PTB Morocco Remus et al. [156]
receptor, beta-1
Lymphotoxin alpha LTA PTB South Africa (Malawi) Fitness et al. [148]
Major histocompatibility HLA PTB South Africa (Venda) Lombard et al. [157]
complex
Mannose-binding lectin MBL2 PTB The Gambia, South Africa Bellamy et al., Fitness
(protein C) 2, soluble (Malawi), Tanzania et al., Soborg et al.
(opsonic defect) [116, 117, 148]
Melanocortin 3 receptor MC3R PTB The Gambia, Cooke et al. [11]
Guinea-Bissau, Republic
of Guinea, South Africa
(Cape Town and Malawi)
Nitric oxide synthase NOS2 PTB South Africa (Cape Town) Moller et al. [75]
2, inducible
BTNL2 rs2076530 SNP No significant association South African Moller et al. [46]
with TB
Pentraxin-related gene PTX3 PTB Guinea-Bissau Olesen et al. [144]
Protein tyrosine PTPN22 PTB Morocco Lamsyah et al. [106]
phosphathase,
non-receptor type 22
(lymphoid)
Purinergic receptor P2X, P2RX7 PTB The Gambia Li et al. [118]
ligand-gated ion
channel, 7
Solute carrier family 11, SLC11A1 Clinical TB, IL10 The Gambia, Republic of Awomoyi et al.,
member 1 production, PTB, TBM Guinea, South Africa Cervino et al., Fitness
(Cape Town and et al., Hoal et al.,
Malawi), Tanzania Soborg et al. [116,
148, 158–160]

Scandinavian Journal of Immunology, 2012, 75, 568–587

T. Qidwai et al. DNA Sequence Variation and Regulation 581
..................................................................................................................................................................

Table 3 Continued.

Gene name Symbol Disease type Population References

PTB The Gambia, Morocco Awomoyi et al., El

Baghdadi et al.
[150, 153, 161]
Solute carrier family 11, SLC11A2 PTB, TBM South Africa (Cape Town) Hoal et al. [160]
member 2
SP110 nuclear body SP110 PTB The Gambia, Tosh et al. [164]
protein Guinea-Bissau, Republic
of Guinea
Surfactant, SFTPA1 PTB Ethiopia Malik et al. [163]
pulmonary-associated
protein A1
Surfactant, SFTPA2 PTB Ethiopia Malik et al. [163]
pulmonary-associated
protein A2
Toll-interleukin 1 receptor TIRAP PTB, TBM Algeria, The Gambia, Dissanayeke et al.,
(TIR) domain containing Guinea-Bissau, Kenya, Khor et al. [111, 165]
adaptor protein Republic of Guinea,
South Africa (Mixed)
PTB Ghana Nejentsev et al. [166]
Toll-like receptor 2 TLR2 PTB, TNF levels Tunisia, Uganda Ben-Ali et al.,
Stein et al. [145, 149]
PTB Guinea-Bissau, South Fitness et al.,
Africa (Malawi) Olesen et al., Stein
et al. [144, 148, 149]
Toll-like receptor 4 TLR4 PTB, TNF levels Uganda Stein et al. [149]
PTB, development The Gambia, Ferwerda et al., Fitness
of TB in HIV Guinea-Bissau, South et al., Newport et al.,
patients Africa (Malawi), Olesen et al. [144,
Tanzania 148, 167, 168]
Toll-like receptor 9 TLR9 PTB Guinea-Bissau Olesen et al. [144]
Tumour necrosis factor TNF PTB South Africa (Malawi) Fitness et al. [148]
Tumour necrosis factor TNFRSF1A PTB, TNF levels Uganda Stein et al. [169]
receptor superfamily,
member 1A
Tumour necrosis factor TNFRSF1B PTB, TNF levels Ghana, South Africa, Moller et al.,
receptor superfamily, Uganda Stein et al. [122, 169]
member 1B
Ubiquitin protein UBE3A PTB The Gambia, Republic of Cervino et al. [159, 171]
ligase E3A Guinea, South Africa
(KwaZulu-Natal)
Vitamin D (1,25- VDR PTB The Gambia, Bellamy et al., Bornman
dihydroxyvitamin D3) Guinea-Bissau, Republic et al., Lombard et al.,
receptor of Guinea, South Africa Olesen et al. [79,
(Venda) 144, 157, 170]
IFNG T+874A and An association Croatian Caucasian Etokebe et al. [63]
G+2109A with disease severity
TLR 2 TLR2-P631H Mutant might confer Croatian Caucasian Etokebe et al. [102]
susceptibility to TB

have been detected in the present work (Tables 1 and 2).
As DNA sequence variations modifies transcriptional reg-
ulation, 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 asso-
ciated 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 poly-
morphism, but IL-10 )592 A ⁄ C promoter’s polymor-
phism which has significant association with TB [128].
This differential association arises as a result of potential
influence 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-

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Scandinavian Journal of Immunology  2012 Blackwell Publishing Ltd.
582 DNA Sequence Variation and Regulation
..................................................................................................................................................................
pass not only multiple alleles located on different genes
and even on different chromosomes but also gene–envi-
ronment interaction. Variation in genotype frequencies
between populations may contribute to inconsistent asso-
ciations 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 path-
way of immune escape [129]. An opposite association of
tuberculosis and autoimmune disease exists. This indi-
cates that autoimmunity is selected against the pressure
of tuberculosis as it provides resistance. Joint investiga-
tion 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 fitness
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 expres-
sion to phenotypic variation and phenotypic variation to
fitness in the wild.
The variations in the DNA region alter the interac-
tion of TF and TFBS, thereby modulating the host par-
asite 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 differ-
ent 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 expres-
sion. 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-
T. Qidwai et al.
scription factors to regions of DNA in Drosophila mela-
nogaster and Drosophila yakuba that have a common
evolutionary origin; however, the relative affinity of
these binding sites often differed between species. Evo-
lutionary 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 dis-
ease susceptibility ⁄ resistance to diseases. We have also
hypothesized that, those polymorphisms that lies in
TFBS might play role in expression divergence, fitness
and evolution. This systematic review summarizes the
associations between genetic polymorphisms and suscepti-
bility 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 findings sup-
port 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 case–control 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 sus-
ceptibility and predicted polymorphisms in TFBS might
play role in expression divergence, fitness and evolution.
Acknowledgment
The author is thankful to the University administration
and Department of Biochemistry, Dr. R. M. L. Avadh
University, Faizabad, for providing a supportive environ-
ment to carryout research activities.
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