GENETIC TESTING AND MOLECULAR BIOMARKERS

Volume 15, Number 7-8, 2011

Mary Ann Liebert, Inc.
Pp. 531536
DOI: 10.1089/gtmb.2010.0240

Associations of the Single-Nucleotide Polymorphisms

of the Mina Gene with the Development of Asthma
in Chinese Han Children: A CaseControl Study
Yun Chen,1 Xiqiang Yang,1 Ying Huang,2 Enmei Liu,2 and Lijia Wang 2

The single-nucleotide polymorphisms (SNPs) of the Mina gene in animals are associated with the development
of Th2-mediated diseases. However, there is no information whether the association occurs in humans. This
casecontrol study aimed at examining the potential association of the SNP of the Mina gene with the development of asthma in Chinese Han children. The DNA genotypes and serum immunoglobulin E and interleukin4 levels of 202 asthmatic patients and 191 nonasthmatic subjects were determined by matrix-assisted laser
desorption ionization-time of flight mass spectrometry method and enzyme-linked immunosorbent assay, respectively. We found that the frequency of the T allele of rs4857304, but not rs832081, rs832078, rs9879532, and
rs17374916, in the Mina gene in asthmatic patients was significantly higher than that of controls ( p = 0.0199).
Using a recessive model, we found that the percentage of patients with TT homozygous rs4857304 was significantly higher than that of controls ( p = 0.0282, odds ratio = 1.568, 95% confidence interval = 1.0482.346).
Further, the mean levels of serum immunoglobulin E and interleukin-4 in the patients with TT genotype of
rs4857304 were significantly higher than that of patients with the G allele ( p = 0.000 and p = 0.03, respectively).
Apparently, the T allele of rs4857304 of the Mina gene may be associated with increased risk for the development
of asthma in Chinese Han children.

Introduction

topy is a natural deficiency in immunological tolerance and atopic subjects are prone to the development of
allergic responses (Gold and Kemp, 2005). The development
of atopy is attributed to many factors such as genetic factors.
The deficiency and aberration of interleukin-10 (IL-10), IL-4
(Li et al., 2008), IL-13 (Black et al., 2009), CD14, and toll receptors (TLRs) (Reijmerink et al., 2010) are associated with the
development of atopy.
The polygenic and phenotypic aberrations are the main
immunological pathogenesis of atopy (Beltrani and Boguneiwicz, 2003). As a result, the increased expression levels of
IL-4 and immunoglobulin E (IgE), a typical T helper type 2
(Th2) response, have been detected in atopic subjects. Th2biased immune responses drive the pathogenic process of
atopy, including asthma, which is one of the most common
chronic airway disorders in children worldwide. The incidence and mortality of asthma are increasing, including in
China (Chen, 2003). The prevalence of asthma in children
reaches 4.63% in Southwest China (Chen, 2003) and about
80% of them are allergic responses to mite allergens. Many
genetic factors are associated with the development of asthma

Divisions of 1Immunology and

(Li et al., 2008). However, the precise genetic factors contributing to the development of asthma in China are not fully
understood.
Notably, the human Mina gene on chromosome 3q11.2
consists of 12 exons spanning 30 kb and encodes a Mina53
protein (Tsuneoka et al., 2002), which is mainly located in the
nucleus and regulates the c-mycrelated cell growth. C-myc
is one of the most widely studied proto-oncogenes (Hoffman
et al., 2002; Pelengaris et al., 2002). Previous studies of Mina53
centered on a variety of human cancer cells (Tsuneoka et al.,
2004; Fukahori et al., 2007; Ishizaki et al., 2007). Recent
studies have shown that Mina53 regulates the expression of
IL-4 in T cells and is related to high susceptibility to Th2driven diseases, such as asthma and leishmaniasis (Hemmers and Mowen, 2009; Okamoto et al., 2009). Interestingly,
the effect of Mina53 on the expression of IL-4 is transcriptionally regulated by the regulatory polymorphisms of the
Mina gene in mice (Okamoto et al., 2009). How the genetic
variants of the Mina gene may regulate the susceptibility of
humans, particularly for Chinese Han children, has never
been explored.
We conducted a casecontrol study to investigate the association of single-nucleotide polymorphisms (SNPs) of the

Respiratory, Childrens Hospital of Chongqing Medical University, Chongqing, China.

531

CHEN ET AL.

DNA extraction and genotyping

Peripheral venous blood samples (2 mL) were obtained from
individual subjects and their genomic DNA was extracted using a DNA extraction kit, according to the manufacturers instructions (Qiagen). Their serum samples were kept at - 20C
for the measurement of serum total IgE and IL-4.
The specific primers for polymerase chain reaction (PCR)
(Table 1) and single-base extension were designed using an
assay designer software package (Sequenom). The SNP genotyping was performed by the massARRAY system using the
matrix-assisted laser desorption ionization-time of flight mass
spectrometry method (MALDI-TOF), according to the manufacturers instructions (Sequenom). Briefly, the PCRs were
performed in duplicate at 94C for 15 min and subjected to 45
cycles of 94C for 20 s, 56C for 30 s, and 72C for 1 min, followed by a final extension at 72C for 3 min. After PCR amplification, the reactions were further extended at 37C for
40 min and inactivated at 85C for 5 min. After treatment with
shrimp alkaline phosphatase, the single-base extension reac-

ACGTTGGATGTCCTCTATGCTCCAAGAGTC
ACGTTGGATGGAGGAATTAGCTGAGGCCTG
ACGTTGGATGGACTCAATTAAAGATGCAGG
ACGTTGGATGGGTCTTTAATAAGATGAGGTC
ACGTTGGATGGCAAACAATAGGCAGCTTAG
ACGTTGGATGTGTAACAAGGTTGCCCAGAC

The Tag SNPs were selected using the TAGGER program in

Haploview version 4.0 software (Broad Institute of MIT and
Harvard). The pairwise tagging approach (Barrett JC et al.,
2005) with a cutoff r2 value of 0.8 was used based on the
HapMap Phase II CHB (Han Chinese in Beijing, China) data.
The SNPs with r2 value 0.8 were considered as Tag SNPs. In
this study, six Tag SNPs of the Mina gene were selected. The rs
accession numbers in the Mina gene were rs832081 (C/T),
rs832078 (C/T), rs4857304 (G/T), rs9879532 (C/T),
rs17374916 (A/G), and rs1532206 (A/G), respectively, which
are available in the NCBI database (www.ncbi.nlm.nih.gov).

ACGTTGGATGGGAATTGGTTGTAGGAGAAG
ACGTTGGATGGGAAGCCTAATACAAACTTGG
ACGTTGGATGCCCAAGACATCTACTACCTG
ACGTTGGATGGGCAGCTACTGAAAAAGAAC
ACGTTGGATGAACCTGAGCCCCTAAGAATG
ACGTTGGATGCCAGTTTTCCCTCTGGATTG

Target polymorphisms of Mina gene in our study

1st-PCRP

A total of 202 Chinese Han children with asthma were recruited from the outpatient service of the Childrens Hospital
of Chongqing Medical University from November 2009 to
May 2010. Individual patients with asthma were diagnosed
according to the guidelines of the global initiative for asthma
(Bateman et al., 2008). The aeroallergens to which individual
patients were allergic were determined by their typical medical history and positive skin prick tests (SPTs). Those patients
displayed positive SPT to at least one allergen.
An additional 191 subjects who were inpatients in the same
hospital were recruited as a control group. Patients who had
nonserious bone fractures were recruited during the same
period for controls. Individuals with asthmatic symptoms or
history or who had other allergic diseases, such as rhinitis and
eczema, or other symptoms or histories of pulmonary diseases or had first-degree relatives with a history of asthma or
atopy were excluded. Those independent subjects who had
cardiovascular or immunologic diseases were also excluded.
Written parental consent was obtained from each participating subject. The experimental protocol was approved by
the Ethics Committees of the Childrens Hospital of
Chongqing Medical University.

Table 1. The Primer Sequences of the Polymerase Chain Reaction and Single-Base Extension

Study subjects

2nd-PCRP

UEP_SEQ

Materials and Methods

rs9879532
rs17374916
rs1532206
rs832081
rs832078
rs4857304

Mina gene with the development of atopic asthma in Chinese

Han children in the southwest of China.

GAGTCTCCTCTGCAAAC
TGCTATCTTTCCCACAAG
ATGCAGGGTTGGATATAA
TGAGGTCACAAATAATCCT
ATAGGCAGCTTAGAATTAACA
TGATTTGTAAGTTGGTAAGAC

532

ASSOCIATIONS OF MINA GENE WITH ASTHMA IN CHINESE CHILDREN

tions were carried out. The genotyping of individual reactions
was determined by MALDI-TOF. The genotype of individual
samples was analyzed using the MassARRAY Typer software
version 3.4 and monitored real time using the MassARRAY
RT software version 3.0.0.4 (Sequenom).
Measurement of serum total IgE and IL-4
The levels of serum IgE and IL-4 were determined by
enzyme-linked immunosorbent assay using human IgE kit,
according to the manufacturers instruction (BioCheck), and
human IL-4 kit (4A Biotech). The detection limits of IL-4 were
7.8500 pg/mL. All values were then transformed to log10
scale for analysis.
Skin prick tests
Individuals responses to 13 common indoor inhalants
(Solu prick SQ; ALK-Abello), namely Dermatophagoides pteronyssinus (Der p), Dermatophagoides farinae (Der f), Bromia tropicalis (Bro t), Canis familiaris, Felis domesticus, Blattella
germanica, American cockroach, mould mix I, mould mix IV,
Artemisia vulgaris, Ambrosia artemisifolia, Pollens IV, and Pollens I, were tested by SPT assays. Their responses to histamine
(10 mg/mL) and saline were used as positive and negative
controls, respectively. Individuals responding to any of the
stimuli with a wheal diameter of 3 mm greater than the negative control were defined as positive (Kawasaki et al., 2008).
Statistical analysis
All polymorphisms were tested for HardyWeinberg
equilibrium (HWE) using the v2 test. A p-value of more than
0.001 was considered an HWE locus. Difference in the genotype and allele frequency between the patients and control
groups was analyzed using the v2 test. The genotype and allele frequencies were obtained by direct counting. The Haploview 4.0 (Kawasaki et al., 2008) was used for the
development of the linkage disequilibrium (LD) blocks, and
the D and r2 values were used to determine pairwise linkage
(Barrett et al., 2005). Haplotypes were assembled using software, according to a standard expectation-maximization algorithm with a partition-ligation approach. Difference in the
haplotype frequency between the patient and control groups
was analyzed by the v2 test.
Assuming a polymorphic site with two alleles a and b,
homozygotes for the major allele (aa) and heterozygotes (ab)
and homozygotes for the minor allele (bb) were coded to a

Table 2. Clinical Characteristics of the Patients

and Controls
Characteristic
Age (year)
Gender (male/female))
Serum total IgE level
(IU/mL)
Geometric mean
Logarithmic scale
a

p < 0.0001 versus control.

IgE, immunoglobulin E.

Asthma
(n = 202)

Controls
(n = 191)

6.97 2.85
106/96

8.14 3.13
109/82

441.63 322.82
2.48 0.46a

113.25 86.32
2.31 0.46

533

continuous numeric variable (0, 1, and 2). A dominant model

was used by comparing the genotypic group of aa + ab with
bb, and the recessive model was defined as contrasting the
genotypic groups of aa versus ab + bb (Yamada et al., 2002;
Ma et al., 2005). All statistical analyses were performed using
SPSS version 13.0 and Haploview 4.0 software. A p-value of
< 0.05 was considered statistically significant.
Results
Clinical characteristics of the patients and controls
To determine the potential association of the SNPs of the
Mina gene with the susceptibility of Chinese Han children to
asthma, a total of 202 asthmatic patients and 191 nonasthmatic subjects were recruited. There was no significant difference in the distribution of age and gender between the
patients and controls (Table 2). Although there was no significant difference in the geometric mean levels of serum IgE
Table 3. The Single-Nucleotide Polymorphisms of the
Mina Gene in the Asthmatic Patients and Controls
Asthma
n = 202
Polymorphisms
rs17374916
Genotype
Allele
rs4857304
Genotype
Allele
rs832078
Genotype
Allele
rs832081
Genotype
Allele
rs9879532
Genotype
Allele
rs1532206
Genotype
Allele

Controls
n = 191

No.

No.

p-Value

AG
AA
GG
A
G

37
162
3
361
43

0.183
0.802
0.015
0.894
0.106

48
140
3
328
54

0.251
0.733
0.016
0.859
0.141

0.2566

TT
GG
GT
T
G

123
7
69
315
83

0.618
0.035
0.347
0.791
0.209

97
13
81
275
107

0.508
0.068
0.424
0.720
0.280

0.0587

CC
TT
CT
T
C

148
4
49
57
345

0.736
0.020
0.244
0.142
0.858

142
2
46
50
330

0.74
0.011
0.242
0.132
0.868

0.7496

CC
CT
T
C

186
16
16
388

0.921
0.079
0.040
0.960

181
10
10
372

0.948
0.052
0.026
0.974

0.2844

CC
TT
CT
T
C

15
97
86
280
116

0.076
0.490
0.434
0.707
0.293

13
85
86
256
112

0.071
0.462
0.467
0.696
0.304

0.8100

AG
AA
GG
A
G

99
51
49
201
197

0.497
0.256
0.246
0.505
0.495

98
53
40
204
178

0.513
0.277
0.209
0.534
0.466

0.6737

0.1368

0.0199a

0.6779

0.2928

0.7304

a
p = 0.0199 versus control, odds ratio = 1.477, 95% confidence
interval = 1.0622.052.
A, adenine; C, cytosine; G, guanine; T, thymine.

534

CHEN ET AL.
Table 4. The Levels of Serum Immunoglobulin E and Interleukin-4 in the Patients
with TT Genotype and Those with G Allele of rs4857304

Groups
TT group
(n = 123)
GG + GT group
(n = 76)

Serum total IgE level

(IU/mL) logarithmic scale

p-Value

Groups

2.5 0.45

0.000

TT group
(n = 18)
GG + GT group
(n = 17)

2.46 0.47

Serum IL-4 level

(pg/mL) logarithmic scale

p-Value

1.95 0.37

0.03

1.84 0.18

IL-4, interleukin-4.

between these two groups of children, the logarithmic mean

levels of serum IgE in the patients were significantly higher
than that of controls ( p < 0.0001).

Table 4). Therefore, the TT genotype of the rs4857304 in the

Mina gene was associated with higher levels of serum IgE and
IL-4 in asthmatic patients.

Associations of the SNPs of the Mina

gene with asthma

LD blocks and haplotype frequencies for the Mina

polymorphisms in patients with asthma and controls

The genotype distributions of all six SNPs were in accordance with HWE in the patients and controls. Further analysis
revealed that there was no significant difference in the distribution of genotype and allele frequencies of the rs17374916,
rs832081, rs832078, rs9879532, and rs1532206 of the Mina gene
between the patients and controls (Table 3). Notably, the
frequency of TT genotype of the rs4857304 of the Mina gene in
patients was higher, but not significant, than that of controls
( p = 0.0587), whereas the frequency of T allele in patients was
significantly higher than that of controls ( p = 0.0199, odds
ratio [OR] = 1.477, 95% confidence interval [CI] = 1.0622.052).
Apparently, the T allele in the rs4857304 of the Mina gene is
associated with increased risk for the development of asthma
in Chinese Han children.

Further LD analysis revealed that four of the six SNPs we

studied in the Mina displayed two haplotype blocks (with
D = 1.0; Fig. 1). The rs832078 and rs1532206 were located in
block 1, whereas the rs17374916 and rs9879532 were in block 2.
Further haplotype analysis showed no statistically significant
difference between the asthmatic patients and controls among
these haplotype blocks. Major haplotypes showing over 5%
frequency in the patients and control are presented in Table 5.

Comparative analysis of the frequency of patients

who were homozygous for the major allele
with those who were homozygous and heterozygous
for the minor allele
Because the rs832081 had only two genotypes (CC and CT),
it was excluded from the analysis of dominant and recessive
models. Using a recessive model, we found that the distribution of rs4857304 variants, but not the other four SNPs, was
significantly different between the patients and controls. The
frequency of children who were homozygous for the T major
allele in asthmatic patients was significantly higher than that
of controls ( p = 0.0282 vs. control, OR = 1.568, 95% CI = 1.048
2.346). Using a dominant model, we found that there was no
significant difference between the frequency of homozygous
and heterozygous for the major alleles with heterozygous for
the minor alleles of these five SNPs between the patients and
controls.
Differences in the levels of serum IgE and IL-4
between the patients with the TT genotype
and with the G allele of rs4857304
Next, we analyzed the levels of serum IgE and IL-4 in patients with the TT genotype and with the G allele of rs4857304.
We found that the mean levels of serum total IgE and IL-4 in
the patients with TT genotype were higher than that of patients with the G allele ( p = 0.000 and p = 0.03, respectively;

FIG. 1. The distributions and locations of the polymorphisms in the chromosomal region. The names of rs numbers
corresponding to their positions are indicated on top. The
linkage disequilibrium blocks are defined by bold black lines.
The different colors of the plots represent the varying degree
of linkage. Red: r2 = 1; intermediate color: 0 < r2 < 1; white:
r2 = 0. Color images available online at www.liebertonline
.com/gtmb.

ASSOCIATIONS OF MINA GENE WITH ASTHMA IN CHINESE CHILDREN

535

Table 5. The Frequency of Mina Haplotypes in the Asthmatic Patients and Controls
Block

Haplotypes

Freq.

Block 1

CA

0.519

CG

0.343

TG

0.138

AT

0.701

AC

0.175

GC

0.123

Block 2

Asthma, controls
Ratio counts

Asthma, controls
Frequencies

Chi square

p-Value

204.0:200.0
204.0:178.0
142.4:261.6
127.4:254.6
57.6:346.4
50.6:331.4
285.6:118.4
265.6:116.4
75.4:328.6
62.4:319.6
43.0:361.0
54.0:328.0

0.505, 0.534

0.664

0.4151

0.353, 0.334

0.312

0.5762

0.143, 0.132

0.169

0.6807

0.707, 0.695

0.127

0.7215

0.187, 0.163

0.736

0.3909

0.106, 0.141

2.214

0.1368

Discussions
Previous studies on the Mina gene products including
Mina53 and its mRNA have concentrated on human cancers
(Pelengaris et al., 2002; Fukahori et al., 2007; Ishizaki et al.,
2007). Notably, the polymorphisms of the Mina gene are associated with the regulation of Mina53 expression, and high
levels of Mina53 are associated with low levels of IL-4 (Hemmers and Mowen, 2009; Okamoto et al., 2009). Given that IL-4 is
a critical factor, contributing to the pathogenic process of
asthma, we studied the potential association of the SNPs of the
Mina gene with the development of asthma in Chinese Han
children. We found that the distribution of the SNPs of
rs4857304, but not rs832081, rs832078, rs9879532, and
rs17374916, in the Mina gene was significantly different between asthmatic patients and control subjects. Further, the T
allele frequency of the rs4857304 in asthmatic patients was
significantly higher than that of controls ( p = 0.0199,
OR = 1.477, 95% CI = 1.0622.052). More importantly, the levels
of serum IgE and IL-4 in patients with TT genotype were significantly higher than that of those with G allele ( p = 0.000),
analyzed using a recessive model. These data suggest that the T
allele of rs4857304 of the Mina gene is associated with increased
risk for the development of asthma in Chinese Han children.
Apparently, the T allele of rs4857304 of the Mina gene may be
used as a potential biomarker for the diagnosis of asthma.
Our findings extend previous observations that the mutations on chromosomes 3q21 (Haagerup et al., 2002), 5q31q33
(Haagerup et al., 2002), and 7p14p15 (Laitinen et al., 2001)
and some SNPs in the IL-4, IL-5, and IL-13 genes are associated with increased susceptibility of individuals to asthma in
different populations (Shirakawa et al., 2000; Kasaian and
Miller, 2008). These, together with different T-cell populations, such as Th17 (Schmidt-Weber et al., 2007), Treg
(Robinson, 2009), and Th9 (Soroosh and Doherty, 2009),
support the notion that many genetic factors contribute to the
development of asthma, which is regulated by several types
of T cells. Given that the TT genotype of rs4857304 of the
Mina gene was associated with increased levels of serum
IgE and IL-4 in asthmatic patients, it is possible that this SNP
may upregulate the expression of IL-4 and promote allergenspecific Th2-dependent B-cell activation and IgE production
in those patients. Conceivably, the TT genotype of rs4857304
of the Mina gene may be used as a biomarker for the predisposition of asthma in Chinese Han Children.

A previous study of a mouse model reveals that the SNPs in

the first exon of the Mina gene regulate the expression of IL-4
(Okamoto et al., 2009). In this study, we obtained these SNPs
located in introns and we found that two constructed LD
blocks did not form a risk haplotype for the development of
asthma in this population. We recognized that our study had
a limitation of a relative small size of sample in one ethnic
group. We are interested in further determining the association of the T allele of rs4857304 of the Mina gene with increased risk for the development of asthma in a bigger
population with multiple ethnic backgrounds and examining
the possible mechanisms by which the T allele of rs4857304 of
the Mina gene regulates the expression of Mina53 and asthmarelated cytokines in Chinese.
In summary, our data suggest that the T allele of rs4857304
of the Mina gene is associated with an increased risk for the
development of asthma and the TT genotype of rs4857304 of
the Mina gene in asthmatic patients is related to high levels of
serum IgE and IL-4 in Chinese Han children. If further confirmed, our findings suggest that the T allele and TT genotype
may be used as a genetic marker for the predisposition of
asthma in Chinese Han children.
Disclosure Statement
All authors of this article have no conflicts of interest
including financial and personal relationships and no potential conflicts with each other, other individuals, and organizations.
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Address correspondence to:

Xiqiang Yang, M.D.
Division of Immunology
Childrens Hospital of Chongqing Medical University
136 Second Zhongshan Road
Yuzhong District
Chongqing 400014
China
E-mail: xiqyang@163.com
Ying Huang, M.D.
Division of Respiratory
Childrens Hospital of Chongqing Medical University
136 Second Zhongshan Road
Yuzhong District
Chongqing 400014
China
E-mail: huangying62@163.com