Hindawi Publishing Corporation

Stem Cells International

Volume 2016, Article ID 8160318, 6 pages
http://dx.doi.org/10.1155/2016/8160318

Research Article
Association between Toll-Like Receptor 4 and
Occurrence of Type 2 Diabetes Mellitus Susceptible to
Pulmonary Tuberculosis in Northeast China
Yuze Li,1,2 Dianzhong Li,2 Jinfeng Zhang,1 Shurui Liu,1 Haijun Chen,3 and Kun Wu1
1

Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin 150081, China
Department of the Fourth Internal Medicine, The Fourth Hospital of Heilongjiang Province, Harbin 150500, China
3
CT Department, Heilongjiang Province Hospital, Harbin 150036, China
2

Correspondence should be addressed to Kun Wu; wukun 15000@126.com

Received 2 December 2015; Revised 3 March 2016; Accepted 13 March 2016
Academic Editor: Yingmei Feng
Copyright 2016 Yuze Li et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The purpose of this study is to explore why type 2 diabetes mellitus (T2DM) patients are susceptible to pulmonary tuberculosis
through detection of serum Toll-like receptor 4 (TLR4 ), an important immune-related receptor, especially in terms of content and
TLR4 gene polymorphism. Patients with T2DM complicated by pulmonary tuberculosis (T2DMTB) were selected as the case group
and T2DM patients without tuberculosis were selected as the control group. Forty patients in each group were randomly selected
and their serum TLR4 levels were detected and compared. Determination of six sites of TLR4 gene polymorphism was carried
out in 238 T2DMTB patients and 310 patients with T2DM, and results showed that the serum TLR4 content of the T2DMTB
group was significantly lower than that of the T2DM group ( < 0.05). The six sites of TLR4 gene polymorphism did not show
significant associations with T2DMTB risk. No statistically significant differences in genotype distributions were observed between
T2DMTB patients and patients with T2DM when studied using the recessive and dominant genetic models. How two diseases with
contradictory nutritional statuses can occur in the same person is difficult to explain from environmental factors perspective alone.
Future research should study the causes of T2DMTB from the perspective of genetics.

1. Introduction
The prevalence of type 2 diabetes mellitus (T2DM) complicated by tuberculosis (TB) (T2DMTB) is rapidly increasing,
resulting in detrimental effects on the economy and human
health.
Clinical symptoms reveal that environmental factors play
important roles in T2DM and TB. Because T2DMTB may
be attributed to multiple causes, clinical experience indicates
the traditional perspective that the two diseases are related
in terms of nutrition. TB is associated with malnutrition,
while T2DM is associated with excess nutrients. Thus, environmental factors, among which nutrition is one of the
most important, alone, cannot explain the pathogenesis of
two seemingly conflicting diseases occurring simultaneously
in the same individual. In this case, genetic factors may
be responsible for the development of T2DMTB [13], but

we are not the first who are aware of host genetic factors
that are important to determine the risk of type 2 diabetes
mellitus complicated by tuberculosis. Garca-Elorriaga et al.
[4] analyzed the association of inflammatory cytokine polymorphisms and T2DMTB in Mexico.
Toll-like receptor 4 (TLR4 ), a pattern recognition receptor, can recognize pathogen-associated molecular patterns
(PAMPs) [5] and exacerbate and release inflammatory
cytokines, such as TNF-, IL-1, IL-6, and IFN- [6]. Mycobacterium tuberculosis presents liposaccharides (LPS), a type
of PAMP. When TLR4 recognizes the LPS of M. tuberculosis,
inflammatory cytokines are induced and released by the
pathway of TLR4 [79]. This pathway is an important element
in the innate immune system of the human body. TLR4 , as an
important mediator of inflammation, can recognize a variety
of pathogens, including Gram-negative and Gram-positive
bacteria [10]. Previous studies have shown that human TLR4

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is a potentially important gene that may affect the onset of
T2DM [1113]. The receptor may be related to susceptibility
to some infections that can induce diseases such as TBs [14
18]. To date, no study has yet reported the association between
TLR4 gene polymorphisms and the risk of T2DMTB in the
Chinese population.
We believe that TLR4 gene polymorphisms are a good
starting point for studying T2DMTB. To be able to establish
preventive measures for high-risk people as far as possible, in this study, we investigate the relationship between
TLR4 gene polymorphisms and T2DMTB risk in Northeast
China.

2. Material and Methods

2.1. Study Subject and Sample Collection. We recruited 238
cases with T2DMTB as the case group and 310 cases with
T2DM as the control group. T2DMTB patient information
was obtained from the Fourth Medical Ward, Heilongjiang
Province Tuberculosis Control Center, from September 2013
to June 2015. T2DM patient information was obtained from
the Second Department of Outpatient Services, Heilongjiang
Province Tuberculosis Control Center, from September 2013
to November 2014.
Subjects with a history of blood-transmitted diseases,
such as AIDS, hepatitis B, hepatitis C, or other endocrine
diseases, were excluded from this study. Blood samples
were taken from the patients, and DNA was obtained
and stored in 193 K. Both doctors and study subjects provided consent to participate in this work, and the Ethics
Committee of Harbin Medical University approved of this
research.
2.2. Immunohistochemical Method. To determine whether
serum TLR4 levels were consistent with the gene expression
level, 40 serum samples were collected from the T2DMTB
group and T2DM group, respectively, according to the
principle of random. Serum TLR4 contents were detected
by using an immunohistochemical method following the
manufacturers instructions (Beijing Cheng Lin Biological
Technology Co., Ltd.).
2.3. Tag SNP Selection and Genotyping. Tag SNPs of TLR4
gene were evaluated and selected by using the HapMap
database (https://hapmap.ncbi.nlm.nih.gov/) with the following criterion: a minor allele frequency (MAF) > 0.05
in the Chinese Han population in the National Center of
Biotechnology Information Database; linkage disequilibrium
(LD) blocks were established by using Chinese LD maps and
2 > 0.8. Six tag SNPs representing the genetic information
of TLR4 were selected for genotyping: rs1927914 located in the
promoter region; rs11536879, rs1927911, and rs1927907 located
in the intron region; and rs11536889 and rs7873784 located in
the 3 -UTR region.
According to the manufacturers instructions, genomic
DNA was extracted from peripheral blood using a Tiangen DNA Blood Mini kit (Tiangen Biotech Co., Ltd., Beijing, China). All SNPs were genotyped using fluorogenic

Stem Cells International

5 -nuclease assay (TaqMan SNP Genotyping Assay, Applied
Biosystems, Foster City, CA, USA). For quality control, 20%
of all of the samples were performed in delicate form randomly for each SNP. The concordance rate of these repeated
samples was 100%.
2.4. Statistical Analysis. Numerical data are expressed as
mean SD. Students t-test was performed to analyze differences between the T2DMTB and T2DM groups.
Fishers exact test was used to evaluate the HardyWeinberg equilibrium (HWE) in the subjects. The chi-square
test or Fishers exact test was used to identify statistical
differences in the distributions of clinic pathological characteristics. Univariate and multivariate unconditional logistic
regression were used to estimate crude and adjusted odds
ratios (ORs) and 95% confidence intervals (CIs), all of
which measured the associations between the risk factors of
T2DMTB compared with T2DM. Two-sided < 0.05 was
considered as statistically significant. Statistical analysis was
carried out by using SAS software (version 9.1.3, SAS Institute,
Cary, NC).

3. Results
3.1. Demographic Characteristics. A total of 548 people participated in this study, including 238 cases of T2MDTB and
310 cases of T2MD. Among the patients, 338 were male and
210 were female. The mean ages of T2DMTB and T2DM
patients were 51.97 11.87 years and 58.73 11.46 years,
respectively. The demographic characteristics of the patients
are shown in Table 1.
3.2. Serum TLR4 Levels of Patients with T2DMTB and
Patients with T2DM. The serum TLR4 levels of subjects with
T2DMTB were significantly lower than those of subjects
suffering from T2DM ( < 0.0001). No differences in the
basic characteristics of the participants, including gender
( = 0.260) and age ( = 0.631), were observed (Table 2).
3.3. Distributions of SNP Genotypes between Patients with
T2DMTB and Patients with T2DM. Genotype distributions
did not show statistically significant deviations from HWE
for all SNPs in this study (Table 3).
3.4. Distribution of Allelic Genes of SNPs between Patients
with T2DMTB and Patients with T2DM. The distributions of
allelic genes of six SNPs of the TLR4 gene were not statistically
significant between patients with T2DMTB and patients with
T2DM. Details of these distributions are summarized in
Table 4.
3.5. SNPs and T2DMTB Risk. The SNPs of TLR4 were not
significantly associated with T2DMTB risk. No significant
differences in genotype distributions between patients with
T2DMTB and patients with T2DM were observed using the
recessive and dominant genetic models (Table 5). However,
potential trends may provide useful information for future
studies. In rs7873784, compared with the GG genotype, the

Stem Cells International

Table 1: Demographic characteristics of the subjects.

Variable
T2DMTB
Age
50
104
5060
73
6070
45
70
16
Gender
Male
167
Female
71
BMI
18.5
35
18.524
112
24
91
Smoking
Yes
132
No
106
Drinking
Yes
108
No
130
Glucose
<5.0
12
5.07.2
48
>7.2
178
Insulin use
Use
112
No use
126
Unclear
0
Hypoglycemic drug use
Use
45
No use
193
Unclear
0

T2DM

Total

value

68
108
80
54

172
181
125
70

<0.0001

171
139

338
210

0.0003

8
64
238

43
176
329

<0.0001

86
224

218
330

<0.0001

94
216

202
346

0.0003

13
88
209

25
136
387

0.0857

196
112
2

308
238
2

<0.0001

224
80
6

269
273
6

<0.0001

Table 2: Serum TLR4 levels of patients with T2DMTB and T2DM.

Variable
Gender (male/female)
Age (years)
TLR4 (ng/mL)

T2DMTB
40 (20/20)
51.17 6.70
15.27 2.52

T2DM
40 (25/15)
51.85 6.20
19.40 1.80

value
0.260
0.631
<0.0001

GC genotype presented lower risks of T2DMTB (ORadjusted =

0.69, 95% CI: 0.421.14, = 0.15). In rs11536879, AG genotype carriers showed decreased risk of T2DMTB compared
with the GG genotype (ORadjusted = 0.68, 95% CI: 0.431.08,
= 0.10).

4. Discussion
A previous study showed that patients with T2DM demonstrated four to eight times increased risk of tuberculosis
compared to patients without T2DM. For instance, TB in
T2DM patients was 5 times more prevalent than in nonT2DM patients in some regions in the USA, 5.4 times more
prevalent than in non-T2DM patients in Australia, and 6.8

times more prevalent than in non-T2DM patients in Mexico

[4].
In the clinic, we discovered that T2DMTB patients
present uneven changes in inflammatory cytokines such as
TNF- and IFN-. Clinical examination of simple TB yielded
a positive IFN- test, but the results of nearly all patients with
T2DMTB were negative. TLR4 is an important element of
the endogenic immune system and it can induce and release
inflammatory cytokines [5]. TLR4 is an important element
of the innate immune system of the human body. Thus,
we hypothesize that serum TLR4 exhibits obvious changes
in T2DMTB patients. We examined TLR4 serum levels in
patients with T2DMTB and patients T2DM to determine
whether TLR4 is involved in the susceptibility of T2DM
patients suffering from TB in Northeast China. While no
study has yet proven that TLR4 polymorphisms are related to
T2DMTB or T2DM, other studies [1922] indicate that TLR4
polymorphisms present statistically significant differences
between healthy people and patients with TB.
Our study results are different from those of Wu et al.
[23], especially in terms of the frequencies of the GG genotype
of SNP rs7873784 in TLR4 (OR = 2.136; 95% CI: 1.312
3.478) and the CC genotype of rs3764879 in TLR8 (OR =
1.982; 95% CI: 1.2923.042). It was also significantly higher
in the TB group than in the healthy group. Arji et al. [24]
found TLR4 interactions influencing protection against TB in
Moroccan patients. The present work and that of Jahantigh
et al. [25] both demonstrated no significant relation between
TLR4 and TLR9 polymorphisms and TB. Sanchez et al. [26]
reported that they did not find any association between
TLR4 polymorphic variants. These findings suggest that the
gene polymorphisms were not involved in any risk factor for
pulmonary TB in the Colombian population [26]. The same
result was obtained by Xue et al. [27], who discovered that
these polymorphisms were rare in the Southeastern Chinese
population and not linked to susceptibility to TB. Newport
et al. [28] also have studied that, but result was that no
association between TLR4 Asp299Gly and TB was observed.
The result of our study showed that it was negative. The
reasons behind this result are first the size of the sample which
was not enough. The second one is the geographic regions
and genetic factors, because we were focused on the people
of Northeast China in our work just only.
The purpose of this study is to determine why patients
with T2DM easily develop pulmonary TB. Thus, we did
not detect TLR4 gene polymorphisms in healthy cases and
we did not compare changes in TLR4 gene polymorphisms
among healthy cases, patients with T2DM, and patients with
T2DMTB. Changes in TLR4 gene polymorphisms may have
already occurred in most patients with T2DM. In this case, a
false negative result may appear if a comparison was carried
out between T2DM patients and patients suffering from
T2DMTB only. Such a phenomenon would also confirm
some reports that T2DM is characterized by chronic inflammation.
Some studies have recently mentioned that the risk
genotypes of rs1927914 are significantly linked with diabetic
foot ulcers [29]; the research team of Singh [30] also found
that the combined genotype risks of TLR4 SNPs rs10759931

Stem Cells International

Table 3: Distributions of SNP genotypes and Hardy-Weinberg equilibrium.

rs7873784
GG
GC
CC
rs11536889
GG
GC
CC
rs1927914
TT
CT
CC
rs1927911
TT
CT
CC
rs1927907
GG
AG
AA
rs11536879
AA
AG
GG

Hardy-Weinberg
value

T2DMTB
No. (%)

T2DM
No. (%)

value

243 (86.17)
35 (12.41)
4 (1.42)

236 (83.69)
45 (15.96)
1 (0.35)

0.19

0.56

0.46

176 (61.97)
93 (32.75)
15 (5.28)

181 (64.41)
86 (30.61)
14 (4.98)

0.83

0.81

0.37

90 (31.91)
145 (51.42)
47 (16.67)

102 (36.17)
140 (49.65)
40 (14.18)

0.50

0.53

0.47

97 (34.28)
139 (49.12)
47 (16.61)

96 (34.16)
148 (52.67)
37 (13.17)

0.48

2.92

0.09

145 (51.24)
123 (43.46)
15 (5.30)

147 (52.31)
119 (42.35)
15 (5.34)

0.96

2.12

0.15

230 (82.44)
41 (14.70)
8 (2.87)

215 (77.62)
56 (20.22)
6 (2.17)

0.20

1.04

0.31

Table 4: Distributions of allelic genes of SNPs between patients with T2DMTB and patients with T2DM.
SNP
rs7873784
rs11536889
rs1927914
rs1927911
rs1927907
rs11536879

Allelic genes
G allele
C allele
G allele
C allele
T allele
C allele
T allele
C allele
G allele
A allele
A allele
G allele

T2DMTB
No.
521
43
445
123
325
229
333
233
413
153
501
57

(odds ratio [OR] 1.50, = 0.05) and rs1927914 (OR 1.48, =

0.05) were significantly linked to retinopathy in T2DM. These
works support the idea that T2DM is a chronic inflammatory
disease. It is possible that T2DM patients already had TLR4
gene polymorphism. Therefore, we considered these points
as the third reason.

T2DM
%
92.36
7.64
78.35
21.65
57.62
42.38
58.83
41.17
72.97
27.03
89.78
10.22

No.
517
47
448
114
344
220
340
222
413
149
486
68

%
91.67
8.33
79.72
20.28
60.99
39.01
60.50
39.50
73.49
26.51
87.73
12.27

value
0.74
0.61
0.43
0.59
0.89
0.30

Two groups of patients were included in our study. For

each group, we concerned about the changing of TLR4 gene
polymorphism and no changing of TLR4 levels in the blood.
The reason of that was hidden behind the changing in the
TLR4 gene, because serum TLR4 is a sensitivity index but not
a specific index. Chronic inflammation could directly lead to

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5
Table 5: Associations between the SNPs of TLR4 and DMTB risk.

Genotype
rs7873784
GG
GC
CC
CC/(GG + GC)
(GC + CC)/GG
rs11536889
GG
GC
CC
CC/(GG + GC)
(GC + CC)/GG
rs1927914
TT
CT
CC
CC/(TT + CT)
(CT + CC)/TT
rs1927911
TT
CT
CC
CC/(TT + CT)
(CT + CC)/TT
rs1927907
GG
AG
AA
AA/(GG + AG)
(AG + AA)/GG
rs11536879
AA
AG
GG
GG/(AA + AG)
(AG + GG)/AA

Crude OR (95% CI)

value

Adjusted OR (95% CI)

value

1.00
0.76 (0.471.22)
3.89 (0.4335.01)
4.04 (0.4536.41)
0.82 (0.521.31)

0.25
0.23
0.21
0.41

1.00
0.69 (0.421.14)
3.16 (0.3330.74)
3.34 (0.3432.38)
0.75 (0.461.22)

0.15
0.32
0.30
0.25

1.00
1.12 (0.781.60)
1.11 (0.522.36)
1.07 (0.512.26)
1.12 (0.791.57)

0.54
0.79
0.86
0.53

1.00
1.04 (0.711.51)
1.08 (0.492.39)
1.07 (0.492.34)
1.04 (0.731.49)

0.85
0.85
0.87
0.82

1.00
1.17 (0.811.69)
1.33 (0.802.21)
1.21 (0.771.91)
1.21 (0.851.71)

0.39
0.27
0.42
0.29

1.00
1.25 (0.851.84)
1.35 (0.802.29)
1.18 (0.731.91)
1.28 (0.891.84)

0.25
0.27
0.49
0.19

1.00
0.93 (0.651.34)
1.26 (0.752.10)
1.31 (0.822.09)
1.00 (0.701.41)

0.70
0.38
0.25
0.98

1.00
0.93 (0.631.36)
1.22 (0.722.09)
1.28 (0.792.08)
0.99 (0.691.43)

0.71
0.46
0.36
0.96

1.00
1.05 (0.751.47)
1.01 (0.482.15)
0.99 (0.482.07)
1.04 (0.751.45)

0.79
0.97
0.98
0.80

1.00
1.03 (0.721.48)
0.95 (0.442.05)
0.93 (0.441.99)
1.02 (0.721.44)

0.86
0.89
0.85
0.90

1.00
0.68 (0.441.07)
1.25 (0.433.65)
1.33 (0.463.89)
0.74 (0.491.12)

0.09
0.69
0.60
0.16

1.00
0.68 (0.431.08)
1.35 (0.454.04)
1.44 (0.484.31)
0.75 (0.481.15)

0.10
0.59
0.51
0.19

Note. Age, gender, BMI, smoking, drinking, insulin use, and hypoglycemic drug use were adjusted.

changes in TLR4 in the blood or other gene polymorphisms

that could lead to TLR4 changes in the blood. Our study was
limited by considering just TLR4 gene polymorphisms. Other
inflammatory gene polymorphisms that promote development of T2DMTB may exist.
The results of this study reveal that TLR4 changes at
the molecular level are insignificant because the changes
at the gene level may be not significant. Our results also
demonstrated no significant link between the six SNPs of
TLR4 studied in this work and the susceptibility of patients
with T2DMTB in Northeast China. Future studies may be
performed to determine the causes of T2DMTB from the
perspective of genetics. We aim to determine the marker gene

polymorphism in T2DM and show how it can be complicated

by TB.

Competing Interests
The authors declare that there are no competing interests
regarding the publication of this paper.

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