Human Immunology xxx (2016) xxxxxx

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journal homepage: www.elsevier.com/locate/humimm

PTPN22 polymorphisms, but not R620W, were associated

with the genetic susceptibility of systemic lupus erythematosus
and rheumatoid arthritis in a Chinese Han population
Liang Tang a,c, Yan Wang a,c, Shui Zheng d, Meihua Bao a,c, Qingsong Zhang a,c, Jianming Li b,a,
a
Department of Human Anatomy, Histology and Embryology, Institute of Neuroscience, Changsha Medical University, Changsha, PR China
b
Xiangya Hospital, Central South University, Changsha, PR China
c
School of Basic Medical Science, Changsha Medical University, Changsha, PR China
d
Key Laboratory for Fertility Regulation and Birth Health of Minority Nationalities of Yunnan Province, Judicial Expertise Center, Yunnan Population and Family Planning
Research Institute, Kunming, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: The present study aimed to detect a possible association between PTPN22 gene polymor-
Received 8 October 2015 phisms and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Chinese Han popula-
Revised 18 January 2016 tion.
Accepted 28 April 2016
Methods: 7 PTPN22 SNPs were genotyped in 358 patients with RA and 713 patients with SLE, as well as
Available online xxxx
564 RA controls and 672 SLE controls by Restriction Fragment Length Polymorphism (RFLP). Association
analyses were conducted on the whole data set. Significant relationships were also examined between
Keywords:
clinical features and SNPs for both RA and SLE.
Protein tyrosine phosphatase nonreceptor
22 (PTPN22)
Results: Rs2476601 was lack of polymorphism with a 60.1% frequency in both SLE and RA patients and
Rheumatoid arthritis (RA) healthy controls in our study. The two SNPs rs1217414 and rs3811021 of PTPN22 shown strong associ-
Systemic lupus erythematosus (SLE) ation with both SLE (rs1217414T: padj = 6.07e!004, OR = 0.57; rs3811021C: padj = 4.68e!005,
Single nucleotide polymorphisms (SNPs) OR = 0.65) and RA (rs1217414T: padj = 2.01e!008, OR = 0.26; rs3811021C: padj = 0.028, OR = 0.70). And
Chinese Han the rs3765598 revealed a strong risk factor for SLE (p = 9.38e!009, padj = 6.57e!008, OR = 1.93), but
not for RA (p = 0.48, OR = 1.12). Moreover, protective haplotype ACTTC in RA (p = 7.73e!016, padj =
5.51!015, OR[95%CI] = 0.02[0.0020.10]) and SLE (p = 8.29e!018, padj = 5.80e!017, OR[95%CI] = 0.11
[0.060.21]) were observed. In addition, the distribution of risk haplotypes ACGTC and GCTTT in RA
(ACGTC: p = 0.0006, padj = 0.004, OR[95%CI] = 1.85[1.292.63]; GCTTT: p = 2.62e!005, padj = 1.85e!004,
OR[95%CI] = 2.40[1.573.65]) and SLE (ACGTC: p = 0.0006, padj = 0.004, OR[95%CI] = 1.85[1.292.63];
ACGTC: p = 7.74e!011, padj = 6.81e!010, OR[95%CI] = 2.21[1.123.34]; GCTTT: p = 2.40[1.573.65],
padj = 2.26e!006, OR[95%CI] = 2.64[1.793.87]) were significant different from that in controls.
Furthermore, significant association was observed between the PTPN22 rs3765598 and antinuclear anti-
bodies 1 (ANA1) in SLE.
Conclusions: Our data provide strong evidence that the rs1217414 and rs3811021 in PTPN22 gene might
be common protective factors contributed to SLE and RA susceptibility in the Chinese Han population.
While, the rs3765598 might increase the genetic susceptibility of SLE, but not RA.
! 2016 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunoge-
netics.

1. Introduction autoimmune disorders that were thought to be caused by complex

interaction of multiple susceptibility genes and environmental fac-
Rheumatoid arthritis (RA [MIM 180300]) and systemic lupus tors and affects approximately 0.32% (1% in Caucasian) and 0.1%
erythematosus (SLE [MIM 152700]) are common complex (0.05% in Caucasian) of the Chinese population respectively [1].
Familiar and twins studies have provided robust evidence for the
Corresponding author at: Department of Human Anatomy, Histology and
role of genetic factors in these diseases [2,3]. It is becoming evident
Embryology, Institute of Neuroscience, Changsha Medical University, Changsha that systemic autoimmune diseases, including RA and SLE, share
410219, PR China. common genetic causative factors in populations of different eth-
E-mail address: ljming0901@sina.com (J. Li). nic or racial origin. The involvement of major histocompatibility

http://dx.doi.org/10.1016/j.humimm.2016.04.021
0198-8859/! 2016 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.

Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021
2 L. Tang et al. / Human Immunology xxx (2016) xxxxxx

complex (MHC) alleles is a piece of evidence that supports the guardians. For the RA patient cohorts, 358 unrelated patients
above hypothesis. However, non-MHC alleles were also required. (Male/female: 94/264; age: 41.7 11.6 years) who met the Ameri-
Recently, a functional polymorphism (rs2476601, Arginine 620 can College of Rheumatology (The American Rheumatism Associa-
Tryptophan (R620W)) in protein tyrosine phosphatase non- tion) 1987 revised criteria for RA [15] were recruited from the first
receptor type 22 (PTPN22), which encodes the lymphoid PTP affiliated hospital, Changsha Medical University. Rheumatoid fac-
(Lyp), was reported to be significantly associated with multiple tor (RF) status was determined for all the patients. Clinical features
autoimmune disorders including type I diabetes (T1D) [4], rheuma- such as erythrocyte sedimentation rate (ESR), C-reactive protein
toid arthritis (RA) [5], systemic lupus erythematosus (SLE) [6] and (CRP), IgA, IgG, IgM were shown in Table 1. For SLE, a total of
Graves disease [7]. This variant (R620W) results in a substitution 713 Patients (Male/female: 102/611; age: 36.7 13.4 years) who
in Arg620Trp that disrupts Lyp binding to Csk [8] and would fulfilled the American College of Rheumatology 1982 criteria for
thereby result in loss of negative regulation of T cell receptor SLE [16] were recruited from the first affiliated hospital, Changsha
(TCR) signaling, and thus autoimmune disorders. The association Medical University. Clinical features such as anti-Sm antibody
between R620W variant of the PTPN22 gene and Type 1 diabetes (anti-Sm), anti-double-stranded DNA (anti-dsDNA), antinuclear
(T1D) in North American and Sardinian populations was first antibody (ANA), ribonucleoprotein (RNP), single strand DNA-
described by Bottini et al. [8]. Subsequently, Begovich et al. binding protein (SSB) were also listed in Table 1. In addition,
observed a significant association between the same PTPN22 1236 unrelated control subjects who without the history of multi-
R620W variant and rheumatoid arthritis (RA) [9]. Furthermore, ple autoimmune diseases (matched for ethnicity, gender and age)
Kyogoku et al. showed an association between the PTPN22 for this study was also enrolled (RA control: 564; SLE control:
R620W and systemic lupus erythematosus (SLE) in a North Amer- 672). All participants were Chinese Han in origin.
ican white population [10]. Together, these data provide com-
pelling evidence for involvement of PTPN22 R620W in 2.2. Genotyping
susceptibility to both systemic and organ-specific autoimmune
diseases. A combination of 7 informative PTPN22 functional or tagging
Interestingly, the R620W was not polymorphic in the Asian SNPs (selected from previous study [11]) was genotyped in both
populations including Chinese Han, Korean and Japanese popula- RA and SLE and healthy controls. Genomic DNA was extracted from
tions. Considering the important role of PTPN22 in the pathogene- peripheral leukocytes using the standard phenolchloroform
sis of autoimmune diseases, more variants except for R620W method. The multiplex PCR were carried out on the ABI Veriti Ther-
should be taken into account in the development of autoimmune mal Cycler (Applied Biosystems, USA) in a total volume of 10 ll,
diseases such as RA and SLE in these populations. As reported in including 1 ll genomic DNA (contain 510 ng DNA), 1 ll 1" PCR
our previous study [11], an intron SNP (rs1217414) was signifi- Buffer(Takara), 3.0 mM Mg2+, 0.3 mM dNTPs, 1 ll primer mix
cantly associated with ankylosing spondylitis (AS) in the Chinese (1 lM each primer), and 1 U Hotstar Taq polymerase (Qiagen
Han population, which might suggest a new susceptible locus of Inc.). Cycling parameters were as follows: 95 "C for 2 min; 10
PTPN22 gene in autoimmune diseases in this population. Moreover, cycles at 95 "C for 20 s, 67 "C !0.5 "C/cycle for 40 s, 72 "C for
there have been limited available studies exploring the association 30 s; 27 cycles at 95 "C for 20 s, 55 "C for 30 s, 72 "C for 1 min; then
between the possible implications of PTPN22 polymorphisms for 4 "C forever. Genotyping was conducted using Restriction Frag-
susceptibility to both RA and SLE [1214]. And none was con- ment Length Polymorphism (RFLP) and 10% of the samples were
ducted in Chinese Han population. In the present study, we aim selected at random to perform repeat assays as genotyping quality
to ascertain whether the PTPN22 polymorphisms were etiologically control. Direct sequencing was analyzed by the ABI 3730XL DNA
relevant to RA and SLE in the Chinese Han population. Sequencer (Applied Biosystems). The restriction enzymes and
sequencing primers for SNPs were listed in Table 1s. Genotype
2. Subjects and methods assignment was successful in >98% of samples tested.

2.1. Sample collection 2.3. Statistical analysis

The study was approved by the Ethical Committee at the Chang- Hardy-Weinberg equilibrium (HWE) was tested in the cases and
sha Medical University (CMUEC-12C0523). Written informed con- controls using a classic chi-square test with 1 degree of freedom.
sents for genetic analysis were obtained from all subjects or their Calculation power was obtained at the 0.05 level of significance,

Table 1
Clinical characteristics of RA and SLE patients.

RA patients SLE patients

Clinical characteristics Mean SD Healthy control Clinical characteristics Mean SD Healthy control
Male/female 94/264 126/438 102/611 97/575
Age (years) 41.7 11.6 (1874 years) 39.6 13.2(2277 years) 36.7 13.4 (1680 years) 31.4 16.9(1982 years)
ESR (mm/h) 33.2 12.5 18.2 11.5 SLEDAI 18.44 8.12
CRP (mg/l) 25 12.2 4.9 13.3 Sm+,% 252/683(36.9%) 0/672(0%)
PLT ("103/lL) 294 11.3 216 18.4 dsDNA+,% 436/674 (64.7%) 0/672(0%)
HLA-B27+,% 1/358 (0.27%) 0/564(0%) Pro+,% 406/547 (74.2%) 0/672(0%)
IgA mg/dl 87.31 21.5 71 15.4 ANA+,% 294/698 (42.1%) 0/672(0%)
IgG mg/dl 104 19.7 55.7 13.3 RNP+,% 292/677 (43.1%) 0/672(0%)
IgM mg/dl 168 24.1 112 14.6 SSB+,% 183/655 (27.9%) 0/672(0%)
ANA+,% 12/358 (3.35%) 0/564(0%) But+,% 506/679 (74.5%) 0/672(0%)
RF+,% 237/308 (76.9%) 0/564(0%) Pho+,% 139/647 (21.5%) 0/672(0%)

Abbreviation: SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SD, Standard Deviation; Sm, Anti-Sm antibody; But, butterfly erythema; Pho, photaesthesia;
ANA, antinuclear antibodies; SSB, single strand DNA-binding protein; dsDNA, Anti-double-stranded DNA; PLT, Platelets; Pro, urine protein; RNP, Ribonucleoprotein; ESR,
erythrocyte sedimentation rate; CRP, C-reactive protein; RF, rheumatoid factor.

Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021
 L. Tang et al. / Human Immunology xxx (2016) xxxxxx 3

assuming an odds ratio (OR) of 1.5 (small effect size) using Quanto

Powerc
(http://hydra.usc.edu/gxe). The statistical analysis was performed

48.2
93.6

86.2
using the PLINK 1.9 (http://pngu.mgh.harvard.edu/~purcell/plink/)

69

53

41

[17]. Individual analyses of associations between PTPN22 polymor-

Abbreviation: SNP, single nucleotide polymorphism; OR, odds ratio; 95% CI, 95% confidence intervals; , not calculated; RA, Rheumatoid arthritis; SLE, Systemic lupus erythematous; Freq., frequency; padj, padjusted.
1.93[1.542.43]
1.11[0.931.31]
1.20[0.951.51]

1.05[0.711.54]
phisms and RA and SLE, as well as autoantibody status were per-

0.57[0.430.76]

0.65[0.540.78]
formed by comparing alleles in cases and controls using Fishers

b
OR(95% CI)
exact test. The corresponding ORs and 95% confidence intervals
(CI) were assessed using a standard logistic regression analysis.
Bonferroni correction was applied to adjust the p value (Padj) in

multiple comparisons. Linkage disequilibrium (LD) analysis was

6.57e!008

4.68e!005
6.07e!004
performed in RA and SLE patients using Haploview program [18].
Analysis of haplotype diversity was performed using the

a
padj
expectation-maximization algorithm (EM). Specific P values and

ORs and 95% confidence intervals (CI) were obtained by comparing

8.67e!005

9.38e!009

6.68e!006
each haplotype with the more common haplotype in the popula-
tion using Fishers exact test. Statistical significance was set at

0.12

0.24

0.78
p < 0.05.

p
Control(freq.)
3. Results

0.095

0.038
0.13

0.27

0.24
0.10
All variants in cases and controls were in Hardy-Weinberg equi-

0
librium (HWE) (p > 0.05). Moreover, the statistical power of the

Case(freq.)
study to detect association with those minor allele frequencies
(MAFs) ranged from 48.9 to 85 in RA population and from 41 to

0.062
0.11
0.17
0.25

0.17
0.04
SLE
93.6 in SLE population (Table 2).

0
Powerc

48.9
3.1. Single-locus association

84
85
85
74
61
50
1.12[0.811.52]
1.12[0.901.58]

1.06[0.861.31]
1.57[0.095.24]
1.10[0.681.77]
0.26[0.170.42]

0.70[0.550.89]
Genotype data for the 7 PTPN22 SNPs successfully typed in the
Chinese Han cases (RA and SLE) and controls were examined by b
OR(95% CI)
single-marker analysis (Tables 2 and 3). The allele frequency of
rs2476601 in both RA and SLE cases and controls (RA vs. controls:
0.1% vs. 0.08%; SLE vs. controls: 0% vs. 0%) was much lower than
that in Caucasian population (>8%) [19] and was similar with the
2.01e!008

previous reports in Asians [11,20]. The results showed no associa-

0.028
tion between the missense SNP (rs2476601, R620W) and neither
a
Padj

RA nor SLE in the Chinese Han population (RA: p = 0.74, OR[95%

CI] = 1.57[0.095.24]; SLE: p > 0.05). Thus, rs2476601 was omitted

Allele distributions of PTPN22 gene polymorphisms in RA and SLE cases and healthy controls.

2.86e!009

from further analysis. Genotype analysis showed that the

0.004

distribution of dominant model of rs1217414 were significant

0.22
0.48
0.57
0.74
0.68

different in SLE, RA and controls, even after the Bonferronis

p

correction (RA: pdom < 0.0001, padj < 0.0001; SLE: pdom = 0.0002,
Power calculations assume a = 0.05 and small effect size (0.1) or OR = 1.5.
Control(freq.)

padj = 0.0014). While, the distribution of dominant and recessive

models of rs3811021 were significant different in SLE and control
0.0008

The Bonferronis correction was carried out to adjust the p value.

0.038

(SLE: pdom < 0.0001, padj < 0.0001; prec = 0.006, padj = 0.042),
0.11
0.14

0.28

0.23
0.09

OR and 95% CI are calculated for the minor allele of each SNP.

but not in RA (p > 0.05). Significant associations between

rs1217414 and rs3811021 and RA (rs1217414: p = 2.86e!009,
Case(freq.)

padj = 2.01e!008, OR [95%CI] = 0.26[0.170.42]; rs3811021:

0.031

0.001

p = 0.004, padj = 0.028, OR [95%CI] = 0.70[0.550.89]) and SLE

0.12
0.11
0.27

0.17
0.04
RA

(rs1217414: p = 8.67e!005, padj = 6.07e!004, OR [95%CI] = 0.57

[0.430.76]; rs3811021: p = 6.68e!006, padj = 4.68e!005, OR
Minor allele

[95%CI] = 0.65[0.540.78]) were observed in further allelic

analysis.
In addition, the distributions of additive, dominant and reces-
G

C
C
T

sive models of rs3765598 were significant different in SLE and con-

1:114113273
1:114124709

1:114095139
1:114106505

1:114089610
1:114089190
1:114068705

trol(SLE: padd < 0.0001, padj < 0.0001; pdom < 0.0001, padj < 0.0001;
prec = 0.0008, padj = 0.007), but not in RA(p > 0.05). Allelic analysis
position

of the SLE cohort revealed that the frequency of the rs3765598T

was significantly higher in patients (17%) compared with controls
(9.5%) (p = 9.38e!009, padj = 6.57e!008, OR [95%CI] = 1.93[1.54
rs1217414
rs1217418
rs3765598
rs1746853
rs2476601
rs1970559
rs3811021

2.43]), but did not differ significantly from that in RA cohort

SNP ID

(11%) and controls (9%) (p = 0.48, OR [95%CI] = 1.12[0.811.52]),

Table 2

which indicated that T allele in rs3765598 might revealed a strong

a

c
b

risk factor for SLE, but not for RA (Table 3).

Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021
4 L. Tang et al. / Human Immunology xxx (2016) xxxxxx

3.2. Haplotype analysis

Abbreviation: SNP, single nucleotide polymorphism; OR, odds ratio; 95% CI, 95% confidence intervals; , not calculated; RA, Rheumatoid arthritis; SLE, Systemic lupus erythematous, Add model, Additive model; Dom model,
0.042
Pb(adj)

0.007
Pairwise LD for the 6 PTPN22 SNPs (except for rs2476601) was

defined using the genotype data from RA and SLE cases separately,

0.0008
model)

0.006
and the summary statistics r2 was calculated using the HaploView

0.15
0.92
program. Five SNPs (rs1217418, rs3765598, rs1746853,
Pa(Rec

5.16,
1.39,
0.94,

0.54,
OR,

rs1970559, rs3811021) were in one block in SLE and RA popula-

tions (Supplementary Figs. 1 and 2). Haplotypes were predicted
<0.0001

<0.0001
for these 5 markers based on the haplotype block using PLINK
0.0014
Pb(adj)

0.14

1.9. Seven haplotypes in RA and SLE separately, each with a fre-

quency >1%, were predicted in both cases and controls accounting
<0.0001

<0.0001 for >95% of all the haplotypes. The haplotype ACTTT was the most
0.0002
model)

0.79
0.02

0.05

common haplotype with a frequency of approximately 65% in RA

Pa(Dom

and SLE. Additionally, we observed marginally significant increase

1.93,
0.58,
0.74,

0.81,

1.06,
0.61,
OR,

in the distribution of haplotype ACGTC and GCTTT in RA (ACGTC:

p = 0.0006, padj = 0.004, OR[95%CI] = 1.85 [1.292.63]; GCTTT:

<0.0001

p = 2.62e!005, padj = 1.85e!004, OR[95%CI] = 2.40 [1.573.65])

0.063
Pb(adj)

and SLE (ACGTC: p = 7.74e!011, padj = 6.81e!010, OR[95%CI]

= 2.21 [1.123.34]; GCTTT: p = 3.23e!007, padj = 2.26e!006, OR

<0.0001

[95%CI] = 2.64 [1.793.87]), even after a Stringent Bonferroni cor-

model)

0.009
0.48

0.36

rection. Moreover, haplotype ACTTC might define protective effect

Pa(Add

to RA(p = 7.73e!016, padj = 5.51!015, OR[95%CI] = 0.02 [0.002

1.44,
6.91,
1.24,

0.55,
OR,

0.10]) and SLE(p = 8.29e!018, padj = 5.80e!017, OR[95%CI] = 0.11

[0.060.21]) (Table 4).

33/297/342

50/226/396
6/127/539
6/174/482
4/121/547
Control(n)

0/52/620
0/0/672

3.3. Association of the PTPN22 polymorphisms with clinical features in

RA and SLE
25/193/495
10/145/558

48/264/401

35/177/501
0/89/624

0/58/655

Regression analysis was also used to evaluate possible correla-

0/0/713
Case(n)

tion between the PTPN22 risk alleles and the specific clinical and
SLE

serological features in RA and SLE shown in Table 5.

ACPA-status was not known for RA patients in previous study.
0.042
Pb(adj)

0.14

Among 358 patients with successful genotyping, 308 patients with

RF information available were divided into two groups by RF sta-

model)

2.13, 0.006

tus: RF-positive RA group and RF-negative RA group. Comparison

0.47, 0.02

of allele frequencies of RF-positive and RF-negative revealed no

Pa(Rec
OR,

significant differences between the two groups (p > 0.05). As to

stratification for ANA1 status in SLE, significant association was

<0.0001

<0.0001

detected between rs3765598T and ANA1 status in ANA1-positive

Distribution of the genotypes of PTPN22 gene polymorphisms in RA and SLE cases and controls.

Pb(adj)

0.14

and ANA1-negative groups (p = 0.006, OR [95%CI] = 1.63[1.15

2.31]). No significant evidence of association between the PTPN22

<0.0001

<0.0001

polymorphisms and other clinical features, either clinical features

model)

0.55

0.84
0.06

0.02

-positive SLE group or clinical features -negative SLE group, was

Pa(Dom

detected.
1.11,
0.24,
0.74,

0.53,

1.04,
0.71,
OR,

The Bonferronis correction was carried out to adjust the P value.

Pb(adj)

4. Discussion
0.07

In the current study, 358 unrelated patients with RA and 713

Dominant model; Rec model, Recessive model; Padj, Padjusted.
model)

1.58, 0.52
1.47, 0.18

0.43, 0.01

patients with SLE were genotyped for polymorphisms in the

PTPN22 gene that was previously reported to be associated with
Pa(Add

P value were calculated using Fishers exact test.

OR,

autoimmune diseases. The data showed that two of the PTPN22

polymorphisms examined (rs1217414 and rs3811021) were signif-

24/316/224

39/183/342
4/112/448
5/158/401
Control(n)

icantly associated with RA and SLE in our material. But no associ-

4/99/461

0/43/512
0/1/563

ation between the functional rs2476601 polymorphism of the

PTPN22 gene and susceptibility to RA and SLE was observed, con-
firming the evidence that the PTPN22 rs2476601 may not predis-
31/130/197

12/101/245

pose individuals to the progress of RA and SLE in the Chinese

6/77/275
4/67/287

1/28/329
1/20/337

0/1/357
Case(n)

Han cohorts. In addition, rs3765598 might revealed a strong risk

factor for SLE, but not for RA. Furthermore, no association was
RA

found between the seven PTPN22 SNPs and most of the clinical
rs1217418,(G)

rs1746853,(G)

rs1970559,(C)
rs3811021,(C)
rs1217414,(T)

rs3765598,(T)

rs2476601,(T)
(minor allele)

and laboratory parameters analyzed (except for rs3765598 and

ANA 1 status in SLE).
SNPs, rs,

Recently, both Genome Wide Association Studies (GWAS) and

Table 3

case-control studies indicated that PTPN22 is second in importance

b
a

in autoimmune disorders, following the MHC. The PTPN22 gene,

Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021
Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus

Table 4
Haplotype analysis of RA and SLE cases and the healthy controls in the PTPN22 genes.

RA SLE
Haplotypea Case(freq.) Control(freq.) Pb padjc OR[95%CI] Haplotypea Case(freq.) Control(freq.) Pb padjc OR[95%CI]
ACGTC 0.098 0.056 0.0006 0.004 1.85 [1.292.63] ACGTC 0.07 0.02 7.74e!011 6.81e!010 2.21 [1.123.34]
ACGTT 0.04 0.01 5.72e!005 3.90e!004 3.53 [1.836.77] ACGTT 0.01 0.01
ACTTC 0.002 0.09 7.73e!016 5.51!015 0.02 [0.0020.10] ACTTC 0.01 0.09 8.29e!018 5.80e!017 0.11[0.060.21]
ACTTT 0.63 0.67 0.05 0.82 [0.661.00] ACTTT 0.64 0.66 0.26 0.90[0.751.08]
ATGTC 0.07 0.08 0.77 0.95 [0.661.35] ATGTC 0.12 0.08 0.0004 0.003 1.64[1.242.15]
GCTTT 0.08 0.04 2.62e!005 1.85e!004 2.40 [1.573.65] GCTTT 0.08 0.03 3.23e!007 2.26e!006 2.64 [1.793.87]
GCGCT 0.03 0.01 0.008 0.06 2.35 [1.224.49] GCGCT 0.03 0.014

Abbreviation: SNP, single nucleotide polymorphism; OR, odds ratio; 95% CI, 95% confidence intervals; , not calculated; RA, Rheumatoid arthritis; SLE, Systemic lupus erythematous; Freq., frequency; padj, padjusted.
a
Haplotype structure of PTPN22 for RA and SLE were rs1217414, rs1217418, rs3765598, rs1746853, rs1970559, rs3811021.
b

L. Tang et al. / Human Immunology xxx (2016) xxxxxx

P value were calculated using Fishers exact test.
c
The Bonferronis correction was carried out to adjust the p value.

Table 5
The association between clinical characteristics in SLE and RA and PTPN22 polymorphisms.

SNPs RA SLE
RF(n = 308) But(n = 679) ANA1(n = 698) dsDNA(n = 674) Anti-Sm(n = 683) RNP(n = 677) Anti-SSB(n = 655)
(pa, OR, 95%CI) (pa, OR 95%CI) (pa, OR 95%CI) (pa, OR 95%CI) (pa, OR 95%CI) (pa, OR 95%CI) (pa, OR 95%CI)
rs1217414 0.56, 0.44(0.121.03) 0.71, 0.90(0.521.56) 0.15, 0.69(0.411.15) 0.11, 0.65(0.381.11) 0.79, 0.93(0.531.62) 0.49, 1.21(0.702.10) 0.92, 1.03(0.561.91)
rs1217418 0.11, 1.33(0.452.41) 0.20, 1.16(0.502.15) 0.69, 1.22(0.612.98) 0.23, 1.29(0.841.97) 0.65, 1.10(0.721.68) 0.96, 0.99(0.651.52) 0.38, 1.17(0.481.72)
rs1746853 0.32, 1.14(0.752.33) 0.41, 0.87(0.631.20) 0.25, 1.19(0.881.61) 0.74, 0.95(0.701.28) 0.72, 1.06(0.771.44) 0.64, 0.93(0.681.27) 0.10, 1.33(0.941.86)
rs1970559 0.66, 0.57(0.211.67) 0.12, 0.45(0.230.87) 0.36, 0.74(0.391.42) 0.81, 0.92(0.471.78) 0.18, 0.59(0.271.28) 0.43, 0.75(0.351.56) 0.83, 0.91(0.402.06)
rs3765598 0.79, 1.37(0.322.55) 0.93, 0.98(0.681.41) 0.006, 1.63(1.152.31) 0.86, 1.03(0.731.45) 0.39, 1.16(0.821.64) 0.69, 1.07(0.751.52) 0.18, 1.29(0.881.90)
rs3811021 0.93, 0.78(0.241.88) 0.62, 1.10(0.751.59) 0.20, 1.25(0.891.76) 0.65, 1.08(0.761.53) 0.29, 1.21(0.851.72) 0.05, 1.42(0.992.01) 0.26, 1.25(0.851.85)

Abbreviations: SNP, single nucleotide polymorphism; OR, odds ratio; 95% CI, 95% confidence intervals; , not calculated; RA, Rheumatoid arthritis; SLE, Systemic lupus erythematous.
RF, rheumatoid factor; But, butterfly erythema; Sm, Anti-Sm antibody; ANA1, antinuclear antibodies 1; SSB, single strand DNA-binding protein; dsDNA, Anti-double-stranded DNA; RNP, Ribonucleoprotein.
a
The alleles were compared between the clinical features positive group and clinical features negative group. P value were calculated using Fishers exact test.

5
6 L. Tang et al. / Human Immunology xxx (2016) xxxxxx

located at chromosome 1 (1p13.11p13.3) region which shows [36,43]. These results suggested a potential role for rs1217414
linkage to RA and SLE, codes for the lymphoid specific tyrosine and rs3811021 in the development of immune-mediated diseases.
phosphatase protein, Lyp. LYP was shown to interact with the neg- There are an increasing number of new pathogenic variants located
ative regulatory kinase, Csk, thereby inhibiting T lymphocyte acti- in non-coding region [44] and studies have suggested that many
vation [2123]. A mutation (rs2476601, 1858C > T) in the PTPN22 disease-related non-coding region SNPs are responsible for aber-
gene encodes the amino acid substitution of arginine to trypto- rant splice processes [4547]. These observations indicated that
phan, which disrupts the Lyp-Csk interaction and therefore results the intronic and 30 -UTR SNPs in the PTPN22 gene might affect the
in autoimmune disorders. splice processes of PTPN22, leading to aberrant expression of
Associations between this polymorphism and SLE susceptibility PTPN22 and thereby influencing the susceptibility to autoimmune
have been identified in different populations from European such diseases. Moreover, although the rs1217414 and rs3811021 may
as Sweden [24], Spanish [25], Crete [12] and Polish [26], as well not have any functional significance itself, it may be linked to some
as from north American [10] and Colombia [13]. Furthermore, functional polymorphisms in PTPN22 gene. This was just a hypoth-
growing bodies of studies have also shown significant association esis, and further study should be carried out to search for more sig-
between this SNP and RA in UK [27] and Western Algerian [28]. nificant evidence.
Thus, PTPN22 C1858T has been now unanimously accepted as a Interesting, rs3765598 was found to be associated with SLE, but
RA and SLE susceptibility locus. The frequencies of the 1858T in not with RA. And significant association was detected between this
SLE (0%) and RA (0.1%) patients and controls (SLE controls: 0%; locus and ANA1 in SLE as well. Rs3765598 is absolute LD with
RA controls: 0. 08%) in the present study were much lower than rs3789604, which was identified to be associated with autoim-
those previously reported for a US-based Caucasian RA and SLE mune diseases. This discovery support that other SNP in 30 UTR out-
cohorts [9]. And, no association was observed between PTPN22 side R620W is associated with human autoimmune diseases. Thus,
1858T and neither SLE nor RA in our samples, which supports the function of this SNP is still hardly known.
the evidence that the PTPN22 1858T might not be the susceptible To evaluate the combined influence of multiple SNPs of the
locus for SLE and RA in the Chinese Han population. The result in PTPN22 gene, association between haplotypes and SLE and RA
present study was contrary to that in Caucasian in UK [27], African was also analyzed in the current study. Statistical association
American [25], Western Algerian [28] and Crete [12], but the same was detected between the haplotype ACGTC, GCTTT and ACTTC
as the results reported in Japanese [29], Indian [30], Iranian [31], and SLE and RA after using Bonferronis correction. Logistic regres-
Turkey [32], Egyptian [33], Colombian [13], Spanish [34] and Rus- sion analysis indicated that Haplotype ACTTC may significantly
sian [35]. This discrepancy may relate to different genetic back- decrease the risk of RA and SLE with odds ratio equal to 0.02 and
ground in sample selection. 0.11 separately. Similarly, Logistic regression analysis indicated
Significant association was observed between the rs2476601 that haplotypes ACGTC and GCTTT significantly increase the risk
and rheumatoid factor(RF) in RF-positive patients and healthy con- of RA and SLE separately. This is the first report on the association
trol with an OR equal to 1.55 (p = 0.03) in Dutch population [36]. between haplotypes containing rs1217418, rs3765598, rs1746853,
And, the susceptible TT and TC genotypes of PTPN22 rs2476601 rs1970559 and rs3811021 of PTPN22 with RA and SLE, which sup-
were strongly associated with rheumatoid factorpositive (RF) dis- ported our previous finding that conducted on Ankylosing
ease in Caucasian [9]. Similar results were reported by Lee et al. spondylitis in Chinese Han population [11]. Never the less, further
[37] and Helen et al. [38]. In contrast with the studies above, no investigation with a larger sample size and haplotype analysis with
association was found between the PTPN22 rs2476601 and the more SNPs should be required to confirm the present result.
presence of rheumatoid factorpositive disease in Spanish RA
patients [14]. Interesting, the rs2476601 was reported to be lack 5. Conclusions
of polymorphism in Asian population including Chinese Han,
Japanese, Indian and Iranian et al. In our study, the frequency of Our results show that two non-coding polymorphisms
rs2476601 was 60.1% in RA indicated that the rs2476601T carriers (rs1217414 and rs3811021) might decrease the genetic suscepti-
were rare in this population. Genetic and environmental hetero- bility of both SLE and RA, and rs3765598 might be a risk factor
geneity between the Caucasian and Chinese Han populations from for SLE but not RA in Chinese Han population, which highlighted
which the RA cohorts might explain the inconsistency. the need to further explore the primary association between
Given the PTPN22 R620W was not polymorphic in the Chinese PTPN22 and autoimmune diseases.
Han population, it is a matter of debate whether the rs2476601
polymorphism is the only PTPN22 disease-associated variant in
Conflict of interest
Asian populations. It is unlikely that a single locus in the PTPN22
gene is solely responsible for the T cell dysfunction in autoimmune
None.
disorders. As reported in our previous study [11], a significant
association was detected between an intron polymorphism
(rs1217414) and ankylosing spondylitis (AS) in the Chinese Han Acknowledgements
population. Before the course of this work, similar studies have
suggested statistically significant associations between the two We are grateful to the SLE and RA patients and control individ-
SNPs (rs1217414 and rs3811021) and autoimmune disorders uals for participating in this study. The Foundation of the Educa-
including SLE and RA. The results of this study supported the pre- tion Department of Hunan (15C0513), the Key Foundation of the
vious findings in UK and European-American populations. Carton Education Department of Hunan (15A023), National Science Foun-
et al. firstly revealed a significant association between the SNP1 dation of Hunan Province (2015JJ6010) and the construct program
(rs1217414) and SNP36 (rs3811021) and RA in two unrelated of the key discipline in Hunan province.
white North Americans populations [39], which was confirmed
by a meta-analysis study and a case-control study later [40,41]. Appendix A. Supplementary data
In addition, a significant association was found between
rs1217414 and Type I psoriasis in UK [42], as well as SLE in Supplementary data associated with this article can be found, in
European-Americans [25]. Moreover, protective effect was also the online version, at http://dx.doi.org/10.1016/j.humimm.2016.
observed between rs3811021 and RA in Caucasian populations 04.021.

Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021
 L. Tang et al. / Human Immunology xxx (2016) xxxxxx 7

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Please cite this article in press as: L. Tang et al., PTPN22 polymorphisms, but not R620W, were associated with the genetic susceptibility of systemic lupus
erythematosus and rheumatoid arthritis in a Chinese Han population, Hum. Immunol. (2016), http://dx.doi.org/10.1016/j.humimm.2016.04.021