Association of PTPN22 / CTLA-4 gene polymorphism to Allergic Rhinitis with
asthma or not in children
Shang-hua Song, Xia Ke*, Xiao-qiang Wang, Yang Shen, Hou-yong Kang, Su-ling Hong*
Department of Otorhinolaryngology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
*both authors are corresponding authors
Correspondence should be addressed to: Su-ling Hong, Department of Otorhinolaryngology, the First Affiliated
Hospital of Chongqing Medical University, Chongqing, China, Tel: (+86 023) 8901 2015, Fax: (+86 023) 8901 2014,
Email: 541856724@qq.com
Key words: AR; asthma; children; SNP; PTPN22; CTLA-4
There are 20844 words and 3 tables in total
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Abstract
Aim: to examine the predisposition of PTPN22 and CTLA-4 gene SNPs to AR and asthma in children.
Methods: A total of 106 AR alone, 112 AR with asthma, and 109 normal children among the Chinese Han were enrolled in the
study. The SNPs of PTPN22 (rs2488457, rs1310182, rs3789604) and CTLA-4(rs3087243, rs11571302, rs11571315, rs231725,
rs335219727, and rs4553808) were genotyped using a PCR-restriction fragment length polymorphism assay.
Results: This study identified increased of the CC genotype and C allele in rs1310182 in AR alone (p=0.002627.OR=5.57, 95%CI
1.82-17.1; p= 0.000266.OR= 2.14, 95%CI 1.42-3.22). For rs3087243, AA genotype and A allele increased in AR with asthma
(p=0.000016.OR=4.90, 95%CI 2.38-10.1; p=0.7x10-6.OR=2.66, 95%CI 1.80-3.92). GG genotype and G allele of rs231725 was
increased in AR alone (p=0.026.OR=2.62, 95%CI 1.12-6.15; p=0.039.OR=1.51, 95%CI 1.02-2.23). But they were significantly lower
in AR with asthma (p=0.00166.OR=0.08, 95%CI 0.02-0.39; p=0.7 x 10-9.OR=0.18, 95%CI 0.11-0.31 respectively).
Conclusions: This study found a significant association between SNPs in PTPN22/ CTLA-4 gene and AR with asthma in Chinese
Han children, which might be the autoimmunity risk for AR and asthma.
Introduction
Allergic rhinitis (AR) is a chronic nasitis induced by IgE-mediated inflammation and regulated by T cells. As an IgE-mediated
inflammation of the upper airway, asthma is common associated with AR. Often, allergic rhinoconjunctivitis and asthma occur
simultaneously in children[1]. About 50% of 5-years-old children with asthma have coexisting rhinitis [2]. While AR is regarded as a
risk factor for asthma [3], allergic rhinitis in children is not always linking with asthma concurrently and the reason is still unknown.
The difference of AR children with asthma or not is researched from environment and gene [4, 5].
As an important element of genetics, Single Nucleotide Polymorphisms (SNP) includes coding sequences of genes, non-coding
regions of genes, and intergenic regions between genes. Polymorphism could influence the development of diseases by changing
the expression of protein. The association of TLR4 and PAI-1 polymorphism with AR and asthma or not had been confirmed [6, 7].
But the SNP about T cell negatively regulate molecule have not been clear. T-cell receptor (TCR) and CTLA-4 are the target of
PTPN22 and CTLA-4 gene, which would play important roles in T cell proliferation and differentiation [8-10].
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The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene, locating at chromosome 1p13.2, encodes the target protein
contains a non-catalytic C-terminus composed of four proline-rich domains and a catalytic N-terminal domain, which is well known
as LYP. By interacting with Csk (C-terminal Src kinase), ZAP70 (zeta- associated protein-70) and Vav (a guanine-nucleotide
exchange factor for the GTPases) involved in the TCR (T-cell receptor) signaling pathway, Lyp could influence the phosphorylation
of T cell responses [11, 12].
The cytotoxic T-lymphocyte–associated antigen (CTLA-4) gene encodes a glycoprotein receptor of the immunoglobulin (Ig) family
expressed on the surface of activated T cells .It maps to chromosome 2q33 which contains a cluster of T-lymphocyte immune
regulating genes: CD28, CTLA-4 and ICOS.As a new candidate for susceptible gene of autoimmune disease, CTLA-4 act as a
negative regulator of T-cell activation by antigen-presenting cells (APC) and of subsequent cellular immunity[13]. CTLA-4 and
CD28 act as members of the same pathway and the CTLA-4 molecule binds the same ligands as CD28 but with at least a 10-fold
greater affinity [14].
PTPN22 and CTLA-4 have been shown to be non-HLA susceptibility genes for various autoimmune diseases, such as rheumatoid
arthritis (RA), type 1diabetes (T1D), systemic lupus erythematosus (SLE), and Graves’ disease (GD) [15-18]. Even so, there is no
evidence about the relationship of these genes and AR in children with asthma or not. In this study, we attempted to examine of the
genetic influences of PTPN22 and CTLA-4 on AR in children and the possible difference with prevalence of asthma or not by
identifying three possible variation sites of PTPN22 and six possible variation sites of CTLA-4.
Materials and methods
Subjects
Overall, 106 children with AR alone (55 boys, 51 girls) and 112 children with both AR and asthma (69 boys, 43 girls) between 1 and
16 years of age were recruited from May 2013 to May 2014. All patients were identified by and treated at the outpatient clinic of the
Department of Otolaryngology Head and Neck Surgery at the Affiliated Children’s Hospital of Chongqing Medical University,
Chongqing, China. The diagnosis of patients was based on the patients’ medical history, symptoms, the presence of a positive skin
prick test (SPT, Allergopharma, Hamburg, Germany), and bronchial provocation test (BPT) according to the ARIA 2008
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guidelines[19].The SPT results were diagnosed in accordance with the recommendations of the Subcommittee on Allergen
Standardization and Skin Tests of the European Academy of Allergy and Clinical Immunology[20]. A positive SPT result was
defined as the formation of a wheal larger than or equal to one half the diameter of the histamine control wheal, and at least 3 mm
larger than the diameter of the negative control wheal. A total of 18 inhaled allergens were tested, including house dust, grass, tree,
mold, food, and cat and dog dander et al. About BPT, the FEV1 decreasing more than 20% is regarded as positive. In contrast,
patients with accompanying systemic disease were excluded from the study. 109 healthy volunteers of the same ethnicity as the
patients were recruited as the control group. The clinical characteristics of the AR and AR with asthma and healthy controls were
assessed at the time of diagnosis and are summarized in Table 1.
Table 1：The clinical characteristics of every group
Characteristics
Gender（boy/girl）
Age（mean<range>）years
Group1(AR)
55/51
5.83(1-16)
Group2(AR+asthma)
69/43
3.72(1-16)
control
55/54
5.77(2-15)
Ethics statement
The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University,
Chongqing, China (Permit number: 2011-201123), and all processes were in agreement with the Declaration of Helsinki. The ethics
authorities provided permission and helped to obtain informed consent from all participants. Written informed consent was obtained
from all participants. Writen Informed consent was also obtained from the next of kin, caretakers, or guardians of any minors
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participating under 18 years in this study.
DNA extraction
Genomic DNA was extracted from EDTA-anticoagulated peripheral blood leukocytes using the Wizard® Genomic DNA Purification
Kit method. Briefly, 300μl of blood was mixed with cell lysis solution. Leucocytes were spun down and lysed with Nuclei Lysis
Solution. The pellet was separated out by Protein Precipitation Solution. Precipitated proteins were removed by centrifugation.
Then, two-filar DNA was separated out by methyl alcohol. The DNA on the EP tube was dissolved in 100μl DNA Rehydration
Solution.
Determination of the PTPN22 and CTLA-4 genotype
We selected the rs2488457, rs1310182 and rs3789604 SNPs in PTPN22 gene as candidate sites, meanwhile, we studied 6 SNPs
rs3087243, rs11571302, rs11571315, rs231725, rs335219727 and rs4553808 in CTLA-4 which have been demonstrated to be
associated with certain immune-related diseases. These SNPs were genotyped using the polymerase chain reaction–restriction
fragment length polymorphism method (PCR–RFLP). The primer sequences and reaction conditions used in this study are shown
in Table 2. The PCR products were incubated with restriction enzymes for 1 or 16 h. The obtained digestion products were
visualized on a 4% agarose gel and stained with Gold View (SBS Genentech, Beijing, China). To confirm the genotyping results,
PCR-amplified DNA samples were examined by direct sequencing (20% of all the blood samples), and the results were 100%
concordant.
Table 2: The primer sequences and reaction conditions
rs number
rs2488457
Primers
F:CCATTGAGAGGTTATGCGAGCT
R: CGCCACCTTGCTGACAACAT
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Restriction enzyme
SacI
rs1310182
F: AAACCCAATGACCAATGACA
Hsp92II
R:AAGCATTTAATTATATGGTGCTGAG
rs3789604
F:GCGAGAGGGGGCTCCTGGCTCGGCCGC
PauI
R: CGGCGGGGGCGCGGCGGAACTACAGC
rs3087243
F: GGACAAATAATGCTTCATGAGTCAGC
TaiI
R: GTTGCCATGACAACTGTAATGCCT
rs11571302
F: CTTCCAGAGGACTTAGGAGAAGCATCTC
MspI
R: TTCTTACAATTCCTCTCAGAGGAAGCTG
rs11571315
F: TTAAAAAGTGAAAAACAAATGTTCCTG
TasI
R: AACTTTAGCCCATGTTATTCTTCTTGT
rs231725
F: CGTCAGATTTGCTGACACTTTAAG
BssSI
R: GATCAAATGGGAAAGAGATTAAGCT
rs35219727
F: GGGCTATAATCACTGCTCACAGGA
ForkI
R: CAGAAGAGAAAACAGTTTGGCAGC
rs4553808
F:CTTCAATTCCAGCATTGATCTCACTCT
R:TATACATGTGCCATGTTGGTGTGATG
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DraI
Statistics analysis
All statistical analyses were performed using SPSS version 19.0 software (SPSS Inc., Chicago, Illinois, USA). P values of less than
0.05 were considered statistically significant. To evaluate the quality of the genotyping data, the Hardy-Weinberg equilibrium (HWE)
for SNP genotype frequencies was tested using a chi-square teat (
test). Logistic regression analysis with odds ratio was used to
compare the association between different genotypes and different phenotypes, adjusting for the children’s age and gender. The
chi-square test was used for differences in prevalence of allergen sensitivity in every two groups. The online software platform
SHEsis (http://analysis2.bio-x.cn/myanalysis.php) was used to analyze the haplotype and probabilities. The association between
genotypes/alleles and the AR risk was estimated by calculating odds ratios (OR) and 95% confidence intervals (CI)
Results
Clinical characteristics of the study participants
The demographics of the cases and controls enrolled in this study are shown in Table 1. There were no significant differences
between the cases and controls in terms of the mean age and gender distribution. 109(50.3%) children in the case groups were
sensitive to house dust mite, 45(20.8%) were sensitive to tree pollen and 64(28.9%) were sensitive to multiple allergens.
Genotype and allele frequencies of PTPN22 polymorphisms in patients and controls
Three SNPs of PTPN22 (rs2488457, rs1310182 and rs3789604) were genotyped in 112 AR with asthma children, 106 AR alone
and 109 healthy controls. Our results showed that they were in Hardy–Weinberg equilibrium and the call rate for the examined
three SNPs was 100%.
An increased frequency of the CC genotype and C allele of rs1310182 in children with AR alone (p=0.002627.OR=5.57, 95%CI
1.82-17.1; p= 0.000266.OR= 2.14, 95%CI 1.42-3.22) (Table 3) were identified, which were not found in the group of AR with
asthma. At the same time, the difference did not exist in the compare between AR alone group and AR with asthma group.
No significant association was found for the rs2488457 and rs3789604 SNP in the two AR groups comparing with the control group.
(Table3)
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Genotype and allele frequencies of CTLA-4 polymorphisms in patients and controls
Six SNPs of CTLA-4 (rs3087243, rs11571302, rs11571315, rs231725, rs35219727, rs4553808) were genotyped in the same
patients and controls.
The results showed that a significantly increased prevalence of AA genotype and A allele of rs3087243 was found in the AR with
asthma children compared to the controls (p=0.000016.OR=4.90, 95%CI 2.38-10.1; p=0.7x10-6.OR=2.66, 95%CI 1.80-3.92).The
difference still exist in the group2 (AR alone) vs. group1 (AR with asthma) (p=0.000012.OR=5.32, 95%CI 2.52-11.2; p=0.6x106.OR=2.70, 95%CI 1.82-3.99).
There were obvious differences in the AR with asthma children and control children concerning the frequencies of rs231725, which
also exist in the AR alone group. A significantly increased prevalence of GG genotype and G allele was found in the AR alone
children compared to the controls (p=0.026.OR=2.62, 95%CI 1.12-6.15; p=0.039.OR=1.51, 95%CI 1.02-2.23). But the frequencies
of the GG genotype and the G allele were significantly lower in the AR with asthma children than in the controls
(p=0.00166.OR=0.08, 95%CI 0.02-0.39; p=0.7 x 10-9.OR=0.18, 95%CI 0.11-0.31 respectively). Comparing children in group2 (AR
alone) and group1 (AR with asthma), the difference was more obvious. The result showed that GG genotype and the G allele in
group2 decreased significantly (p=0.7 x10-5.OR=0.03, 95%CI 0.01-0.15; p=0.2 x10-13.OR=0.12, 95%CI 0.07-0.21). (Table3).
No significant association was found for the other four CTLA-4 SNPs in two case groups compared with healthy control. (Table3).
Table3: Statistics analysis. (Group1 is the children with AR alone; group2 is the children with AR and asthma)
SNP
Rs2488457
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Genotype
GG
Group1
18
Group2
18
Control
19
Group1 VS. Control
Group2 VS. Control
Group2 VS. Group1
aOR95%CI
P value
aOR95%CI
P value
aOR95%CI
P value
-
-
-
-
-
-
Rs1310182
RS3789604
rs3087243
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CG
56
63
57
1.03(0.49-2.19)
0.930
1.29(0.61-2.77)
0.504
1.23(0.58-2.64)
0.585
CC
32
31
33
1.03(0.45-2.34)
0.939
1.10(0.48-2.51)
0.820
1.06(0.46-2.43)
0.894
G
92
99
95
-
-
-
-
-
-
C
120
125
123
1.01(0.69-1.48)
0.950
1.01(0.69-1.48)
0.950
1.00(0.68-1.46)
0.994
TT
30
62
58
-
-
-
-
-
-
CT
62
47
46
2.59(1.43-4.69)
0.001626
0.91(0.52-1.57)
0.731
0.37(0.21-0.66)
0.000815
CC
14
3
5
5.57(1.82-17.1)
0.56(0.13-2.49)
0.451
0.10(0.03-0.40)
0.000990
T
122
171
162
-
-
-
-
-
-
C
90
53
56
2.14(1.42-3.22)
0.000266
0.87(0.56-1.35)
0.536
0.43(0.28-0.64)
0.000049
TT
75
84
74
-
-
-
-
-
-
GT
28
24
30
0.93(0.50-1.71)
0.809
0.71(0.38-1.32)
0.275
0.74(0.39-1.39)
0.353
GG
3
4
5
0.58(0.13-2.53)
0.470
0.67(0.17-2.62)
0.565
1.12(0.24-5.21)
0.887
T
178
192
178
-
-
-
-
-
-
G
34
32
40
0.85(0.51-1.41)
0.53
0.73(0.44-1.22)
0.234
0.84(0.50-1.43)
0.528
GG
41
20
45
-
-
-
-
-
-
AG
44
40
40
1.20(0.66-2.20)
0.556
2.24(1.12-4.45)
0.022
1.92(0.96-3.83)
0.065
Rs11571302
Rs11571315
Rs231725
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AA
21
52
24
0.95(0.46-1.96)
0.892
4.90(2.38-10.1)
0.000016
5.32(2.52-11.2)
0.000012
G
126
80
130
-
-
-
-
-
-
A
86
144
88
1.00(0.68-1.47)
0.993
2.66(1.80-3.92)
0.7x10-6
2.70(1.82-3.99)
0.6x10-6
AA
23
9
17
-
-
-
-
-
-
AC
50
62
54
0.66(0.31-1.39)
0.277
2.09(0.85-5.09)
0.106
3.01(1.27-7.12)
0.012
CC
33
41
38
0.63(0.29-1.38)
0.248
2.04(0.81-5.16)
0.131
3.02(1.22-7.44)
0.017
A
96
80
88
-
-
-
-
-
-
C
116
144
130
0.81(0.55-1.19)
0.293
1.23(0.84-1.82)
0.288
1.46(0.99-2.14)
0.056
AA
31
43
39
-
-
-
-
-
-
AG
59
45
43
1.72(0.93-3.20)
0.085
0.90(0.48-1.67)
0.736
0.53(0.29-0.98)
0.044
GG
16
24
27
0.75(0.34-1.62)
0.458
0.76(0.37-1.54)
0.444
1.06(0.48-2.34)
0.883
A
121
131
121
-
-
-
-
-
-
G
91
93
97
0.94(0.64-1.37)
0.740
0.85(0.58-1.25)
0.41
0.93(0.63-1.36)
0.698
AA
34
94
45
-
-
-
-
-
-
AG
50
16
53
1.23(0.67-2.23)
0.495
0.14(0.07-0.27)
0.8 x10-8
0.11(0.06-0.23)
0.1 x10-8
GG
22
2
11
2.62(1.12-6.15)
0.026
0.08(0.02-0.39)
0.00166
0.03(0.01-0.15)
0.7 x10-5
Rs35219727
Rs4553808
A
118
204
143
-
-
-
-
-
-
G
94
20
75
1.51(1.02-2.23)
0.039
0.18(0.11-0.31)
0.7 x 10-9
0.12(0.07-0.21)
0.2 x10-13
GG
102
106
106
-
-
-
-
-
AG
4
6
3
1.35(0.29-6.21)
0.699
1.91(0.46-7.93)
0.372
1.43(0.39-5.24)
0.592
G
208
218
215
-
-
-
-
-
-
A
4
3
3
1.34(0.30-6.09)
0.701
1.89(0.46-7.72)
0.377
1.42(0.39-5.12)
0.596
AA
58
79
72
-
-
-
-
-
-
AG
44
31
33
1.68(0.94-2.99)
0.078
0.88(0.49-1.60)
0.686
0.53(0.30-0.94)
0.030
GG
4
2
4
1.32(0.31-5.63)
0.710
0.47(0.08-2.67)
0.468
0.40(0.07-2.28)
0.303
A
160
189
177
-
-
-
-
-
-
G
52
35
41
1.42(0.89-2.27)
0.142
0.82(0.50-1.35)
0.441
0.59(0.36-0.95)
0.030
Discussion
In this study, we investigated the PTPN22 and CTLA-4 gene polymorphisms in AR with asthma or not and demonstrated a novel
association between SNPs of rs1310182 in the PTPN22 gene and rs3087243, rs231725 in the CTLA-4 gene in a Chinese Han
children population. For rs1310182, the CC genotype and the C allele were risk factors for children with AR alone. The AA
genotype and the A allele of rs3087243 gene were significative in AR with asthma children. Furthermore, for rs231725, we found
that the GG genotype and the G allele were positively correlated in both two groups which may be a potential risk factor for AR
alone but be a protect factor in AR with asthma children. To the best of our knowledge, this is the first study to evaluate an
11 / 15
association between PTPN22 SNPs rs1310182, CTLA-4 SNPs rs3087243, rs231725 and AR with asthma or not in children of
Chinese Han population.
AR, as a common inflammatory disorder of the upper airway, is the result of a complex interplay between multiple genetic and
environmental factors resulting in the dysregulation of the immune system[21]. The historic perspective of allergic rhinitis and
asthma as distinct and separate entities is being displaced by current thinking that they are better described as a continuum of
inflammation involving a single common pathway[22], or one airway, one disease[1]. To date, data point toward a systemic link
between the upper and lower airways[23]. To explore the genetic influences of PTPN22 and CTLA-4 on AR with asthma or not in
children, we chose rs2488457, rs1310182, rs3789604 ,rs3087243, rs11571302, rs11571315, rs231725, rs35219727, rs4553808 as
candidate sites, based on the results of some previous studies[24-26].
These data demonstrated an association of SNPs rs1310182 in the PTPN22 gene both in AR alone and AR with asthma in children,
indeed the difference existed between two groups. However, no significant association was observed of rs2488457 and rs3789604
polymorphisms. The results suggest that the genetic background of AR with asthma or not might be similar to those of RA, SLE and
VKH. Meanwhile the contact appeared in the SNPs rs3087243 and rs231725 in the CTLA-4 of AR with asthma, which is same as
Sjogren’s syndrome and T1D [27, 28].There was no data show the association between other sites and the cases.
Compared with the date we gained from our study before about AR in adult, there were a lot of difference .SNPs rs2488457 in the
PTPN22 gene was not be found in children, which was existed in adult. Also the obvious differences of the SNPs rs11571302 in the
CTLA-4 disappeared. These results might suggest the discrepancy of SNPs in different ages which owing to the imperfection of
immune system of children. Even there may is various pathogenesis of AR between children and adult.
The polymorphisms of PTPN22 and CTLA-4 maybe essential to the disease risk of AR with asthma or not in children, distinguishing
from adult, supporting the importance of PTPN22 and CTLA4 as an autoimmune susceptibility locus. But the definite way how they
play a part had still not been making clearly. We just could conjecture that PTPN22 and CTLA-4 SNPs might change the
expression of TCR and CD4+CD28+ Treg cell by regulating and controlling related mRNA according the study on these two genes
using gene knocking- out technology[12, 29].
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To increase the credibility of the results, we adept measures to avoid the influence of confounding factors. Participants were
chosen by using strict guidelines and genotyping results were confirmed by direct sequencing. We observed a novel association
between SNPs rs1310182 of PTPN22, rs3087243 and rs231725 of CTLA-4 and AR with asthma or not in children of Chinese Han
population. There were some limitations to our study which need to be further deliberated such as case load, environmental factors
and so on. The embedded function analysis study about the protein level of PTPN22 and CTLA-4 is necessary for drawing a certain
conclusion about the influence of these polymorphisms on the cytokine levels.
In conclusion, the study afford some proof of the association of PTPN22 and CTLA-4 with AR with asthma or not in children,
suggesting that there should be implication of these genes in the susceptibility to AR or asthma.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (81300811) and National Key Clinical Specialties
Construction Program of China.
Conflict of Interest
The authors declare no financial or other conflicts of interest regarding the content of this article.
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