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Contents lists available at ScienceDirect

Journal of Dermatological Science

journal homepage: www.jdsjournal.com

Association between single nucleotide polymorphisms IL17RA

rs4819554 and IL17E rs79877597 and Psoriasis in a Spanish cohort.
Ana Batallaa , Eliecer Cotob,e , Leire González-Laraa , Daniel González-Fernándeza ,
Juan Gómezb , Tamara F. Arangurenb , Rubén Queiroc , Jorge Santos-Juanesa ,
Carlos López-Larread, Pablo Coto-Seguraa,e,*
a
Department of Dermatology II, Hospital Universitario Central Asturias, Calle Carretera de Rubín, s/n, 33011 Oviedo, Spain
b
Department of Molecular Genetics, Hospital Universitario Central Asturias, Calle Carretera de Rubín, s/n, 33011 Oviedo, Spain
c
Department of Rheumatology, Hospital Universitario Central Asturias, Calle Carretera de Rubín, s/n, 33011 Oviedo, Spain
d
Department of Immunology, Hospital Universitario Central Asturias, Calle Carretera de Rubín, s/n, 33011 Oviedo, Spain
e
Department of Medicine, Universidad de Oviedo, Calle San Francisco, 1, 33003 Oviedo, Spain

A R T I C L E I N F O A B S T R A C T

Article history: Background: The IL17 pathway plays an important role in the pathogenesis of psoriasis (PsO).
Received 13 February 2015 Objectives: To determine whether the variation at the IL17 pathway genes was linked to the risk for PsO or
Received in revised form 29 April 2015 had an effect on disease severity and the risk for Psoriatic arthritis (PsA).
Accepted 23 June 2015
Methods: Cross-sectional observational study of 580 psoriasis patients and 567 healthy controls who
were genotyped for six single nucleotide polymorphisms (SNPs) in the IL17RA (rs4819554, rs879577),
Keywords: IL17A (rs7747909), IL17F (rs763780, rs2397084), and IL17E (rs79877597) genes.
Gene polymorphism
Results: We found significant higher frequencies of IL17RA rs4819554 G carriers among the patients
Genetic susceptibility
Genotypes
(OR = 1.33, 95%CI = 1.05–1.69; p = 0.017). The IL17RA rs4819554 G allele and IL17F rs2397084 TT genotype
IL17 pathway genes were significantly more frequent among Cw6 positive patients (p = 0.037 and p = 0.010, respectively). The
Psoriasis IL17E rs79877597C allele was significantly more common among patients with severe forms of PsO
Psoriatic arthritis (p = 0.010; OR = 2.42, 95%CI = 1.23–4.76), and the CC genotype with the presence of arthritis (p = 0.032;
OR = 1.50, 95%CI = 1.04–2.18).
Conclusions: We identified the IL17RA rs4819554 SNP as a risk factor for PsO. The IL17E rs79877597 SNP
was a modifier of the risk for PsO disease severity and PsA.
ã 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights
reserved.

1. Introduction to this well characterized genetic association, other immunological

Psoriasis (PsO) is a common, chronic inflammatory skin disease
affecting approximately 2–4% of the population [1]. PsO is
considered a multifactorial disease in which the genetic back-
ground interacts with environmental factors to define the
individual’s risk [2]. The genetic component affects not only the
overall risk, but also the clinical type, age of disease onset, severity,
or the risk for psoriatic arthritis (PsA) [3]. The first locus for PsO
(PSORS1) was mapped to human chromosome 6p21.3, and further
studies identified the Major Histocompatibilty Locus
HLA_Cw6*0602 allele as the main PsO-risk factor [4]. In addition
* Corresponding author at: Hospital Universitario Central Asturias. c/ Calle
Carretera de Rubín, s/n, 33011 Oviedo, Spain.
E-mail address: cotopablo@uniovi.es (P. Coto-Segura).
relevant genes have been linked to the risk for PsO and pointed to
new pathways implicated in this disease [5].
The IL-17 family comprises a group of cytokines with an active
role on the acute and chronic immune responses [6]. This family
consists of six members (IL-17A to F) and five receptors (IL-17RA to E)
[7]. IL-17A is the founding member and defines a new subset of CD4+
effector T (Th17) cells. This cytokine induces the production of
inflammatory mediators from epithelial and endothelial cells and
fibroblasts [7,8]. It also mobilizes, recruits and activates neutrophils,
thus connecting innate and adaptive immunity [9]. It has been
shown that the cells that secrete IL-17 are present in psoriatic lesions
in a higher number than in normal skin [10]. As well, increased levels
of circulating IL-17-producing cells have been found in psoriatic
patients, and higher levels of IL-17 were found in lesional skin and
plasma of psoriatic patients compared to healthy individuals
[10–12]. In PsO, both IL-17A and IL-17F have proinflammatory

http://dx.doi.org/10.1016/j.jdermsci.2015.06.011
0923-1811/ ã 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: A. Batalla, et al., Association between single nucleotide polymorphisms IL17RA rs4819554 and IL17E
rs79877597 and Psoriasis in a Spanish cohort., J Dermatol Sci (2015), http://dx.doi.org/10.1016/j.jdermsci.2015.06.011
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effects on keratinocytes and neutrophils. Keratinocytes express IL-
17RA and respond to IL-17A and IL-17F producing, among others, IL-
6, GM-CSF, AMPs and other chemokines that are positively regulated
in PsO [1,12]. IL17E, also known as IL25, is mainly expressed by Th2
cells and is implicated in the production of Th2 cytokines and the
subsequent recruitment of eosinophils [13,14]. IL17E also has
inhibitory properties over Th17 cells [15].
Several common polymorphisms in the IL-17 family genes have
been linked to the risk for developing autoimmune [16–18],
inflammatory [8,19], or infectious [20,21] diseases, and even for
susceptibility to several neoplasms [22,23]. To our knowledge
there are few reports about the effect of the polymorphisms at IL17/
IL17RA axis on the risk for developing PsO or PsA [24,25]. Thus, our
main aim was to determine whether common DNA variants at
IL17RA, IL17A, IL17F and IL17E genes were associated with the risk
for developing PsO or have an effect on disease severity or the risk
for PsA. The selection of the targeted single nucleotide polymor-
phisms (SNPs) was made after a carefully review of the existing
literature (Table A.1).
2. Subjects and methods
2.1. Patients and controls
This was a cross-sectional and retrospective observational
study including a total of 580 patients with chronic plaque PsO
(mean age 47
15 years; 54% men) and 567 controls (mean age
51
14 years; 55% men). PsO patients were recruited through the
Department of Dermatology of Hospital Universitario Central
Asturias (HUCA) between January 2007 and August 2014. The
control group consisted of non-related healthy individuals
recruited through the Blood Bank and the Department of
Dermatology of HUCA. All the participants were Caucasians from
the region of Asturias (Northern Spain, total population 1 million),
older than 18 years old, and gave their written informed consent to
participate in the study. Ethics approval was also obtained by the
Ethical Committee of HUCA. Patients’ main demographic and
clinical characteristics are summarized in Table 1. PsO was
diagnosed based on clinical findings by two independent
dermatologists, and the disease was defined as severe or non-
severe according to the Psoriasis Area and Severity Index (PASI;
severe, a PASI score  10). In all patients, PASI values were recorded
previously to the onset of PsO therapy. The existence of arthritis
was assessed by a rheumatologist according to Moll and Wright or
more recent CASPAR criteria [26]. Demographic and clinical data
including age of disease onset (early onset considered if the age of
Table 1
Main characteristics of the 580 patients with Psoriasis.
Main characteristics of the 580 patients with Psoriasis
Gender (male/female) 313 (54%)/267 (46%)
Age (years) (mean
SD) 47.09
14.66
HLA-Cw6 presence 241 (42%)
Family history of psoriasis* 297 (52%)
Early onset psoriasisz 427 (74%)
Age (median)
HLA_Cw6 presence
Late onset psoriasisz 153 (26%)
Age (median)
HLA_Cw6 presence
#
Mild–to–moderate psoriasis 287 (49%)
Severe psoriasis# 293 (51%)
Arthritis 170 (29%)
PASI: Psoriasis Area and Severity Index; SD: standard deviation.
*
The total number of patients in which the variable of family history of psoriasis
was recorded was of 567 due to doubtful cases that could not be demonstrated.
z
Early onset psoriasis: age  40 years; Late onset psoriasis: age > 40 years.
#
Mild–to–moderate psoriasis: PASI < 10; Severe psoriasis: PASI  10.
Please cite this article in press as: A. Batalla, et al., Association between single nucleotide polymorphisms IL17RA rs4819554 and IL17E
rs79877597 and Psoriasis in a Spanish cohort., J Dermatol Sci (2015), http://dx.doi.org/10.1016/j.jdermsci.2015.06.011
PsO onset was below or equal to 40 years), duration of PsO, nail
involvement, familial history of PsO (familial PsO if there was at
least one first- or second-degree affected relative) and other
comorbidities different from PsA were also collected. All the
patients had been previously genotyped for HLA-Cw6 (PSORS1)
[27].
2.2. SNPs genotyping
The selection of the SNPs was based on previous reports that
described a positive association with diseases (Table A.1). The
locations and predictive effects of the selected SNPs are shown in
Table A.2.
SNPs were then determined in all the patients and controls
trough Real Time Taqman assays (www.appliedbiosystems.com):
rs4819554 and rs879577 in IL17RA, rs7747909 in IL17A, rs763780
and rs2397084 in IL17F, and rs79877597 in IL17E.
2.3. Statistical analysis
Statistical analysis was carried out using the R software system
(version 3.0.2). The x2 test was used to compare genotype and
allele frequencies between the groups and to determine the
deviation of the genotype frequencies from the Hardy–Weinberg
equilibrium. Odds ratios (OR) and their 95% confidence intervals
(CI) were also calculated. The Student’s t test was used to compare
quantitative variables between the groups. We performed
multivariate logistic regression analysis to adjust for risk factors.
A p < 0.05 was considered as statistically significant.
3. Results
The observed genotype frequencies for the six SNPs did not
deviate from the Hardy–Weinberg equilibrium in both, patients
and controls. Minor allele frequencies (MAF) for the six genes in
patients and controls are shown in Table 2. Only the IL17RA
rs4819554 G showed significant differences between the two
groups (p = 0.017).
We found significantly different allele and genotype frequen-
cies for the IL17RA rs4819554, where G carriers (AG + GG) were
significantly more common among PsO patients (p = 0.017), with
an OR = 1.33 (95%CI = 1.05–1.69), with respect to the control group
(Table 3). This SNP was also significantly associated with the Cw6
status: 48% of the Cw6-positive patients were G-carriers compared
to 40% of G-carriers among the Cw6-negative patients (p = 0.037;
OR = 1.43, 95%CI = 1.02–1.99) (Table 3). We did not find significantly
differences between patients and controls for the IL17RA rs879557
allele/genotypes, but the rs879557 T-carriers were also more
frequent among the Cw6-positive cases, although at a non-
significant difference (Table A.3). A relation with Cw6 was also
identified in the case of IL17F rs2397084 SNP, where PsO patients
with the TT-genotype were more common among the Cw6-
positive patients (OR = 2.07; 95%CI = 1.19–3.60; p = 0.010) (Table 4).
Nevertheless, allele and genotype frequencies of these three above
mentioned SNPs, IL17RA rs4819554, IL17RA rs879557, and IL17F
19 rs2397084, did not differ between patients according to disease
208 (49%)
severity, presence of PsA, or other demographic or clinical
52 characteristics (Tables 3–4, Table A.3.)
33 (22%) Additional significant differences were observed for the IL17E
rs79877597 SNP (Table 5). Allele C carriers presented a more
severe form of PsO (p = 0.010; OR = 2.42, 95%CI = 1.23–4.76). Also
the CC genotype was a significant risk factor for PsA (p = 0.032;
OR = 1.50, 95%CI = 1.04–2.18).
Regarding IL17A rs7747909 and IL17F rs763780 SNPs, no
significant allele or genotype differences between patients with
PsO and healthy controls were evidenced. In addition, no
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Table 2
Minor allele frequencies (MAF) for the six genes of the study.

Minor allele frequencies (MAF) for the six genes of the study

Il17RA-rs4819554: G IL17RA-rs879577 : T Il17A–rs7747909: A Il17F–rs763780: C Il17F–rs2397084: C Il17E–rs79877597: A

Controls n = 567 (%) 0.20 0.23 0.25 0.06 0.08 0.21
Patients n = 580 (%) 0.24 0.25 0.27 0.05 0.07 0.24
PASI  10 n = 293 (51%) 0.24 0.26 0.26 0.05 0.07 0.22
PASI < 10 n = 287 (49%) 0.25 0.24 0.28 0.05 0.07 0.27
PsA n = 170 (29%) 0.25 0.26 0.26 0.06 0.06 0.20
No PsA n = 410 (71%) 0.24 0.24 0.27 0.05 0.07 0.26
Cw6-positive n = 241(42%) 0.28 0.28 0.27 0.04 0.04 0.26
Cw6-negative n = 339 (58%) 0.22 0.23 0.27 0.06 0.08 0.23
Family history of PsO n = 297 (52%) 0.26 0.25 0.27 0.05 0.05 0.24
No family history of PsO n = 270 (48%) 0.22 0.24 0.27 0.06 0.09 0.25
Early onset PsO n = 427 (74%) 0.25 0.25 0.28 0.05 0.06 0.25
Late onset PsO n = 153 (26%) 0.22 0.22 0.25 0.07 0.08 0.24

significant associations between these SNPs and other demo-

Table 3 graphic or clinical data were detected (Tables A.4–5).
Genotype and minor allele frequencies (MAF) for the Il17RA (rs4819554) SNP.

Il17RA-rs4819554 4. Discussion
AA AG GG A G
The current pathogenic model of PsO emphasizes the IL-23/
Controls n = 567 (%) 360 (63) 187 (33) 20 (4) 0.80 0.20
HW controls 363 181 23 IL17 axis.[28] Genome wide association studies (GWAS) have
Patients n = 580 (%)* 328 (57) 221 (38) 31 (5) 0.76 0.24 linked PsO-risk to SNPs at the IL-23R and ACT1, two regulators of
HW patients 335 212 33 IL-17 production and IL-17-mediated signaling [29,30]. In addi-
PASI  10 n = 293 (51%) 166 (57) 112 (38) 15 (5) 0.76 0.24 tion, a new subset of anti-psoriatic agents against IL-17 or its
PASI < 10 n = 287 (49%) 162 (56) 109 (38) 16 (6) 0.75 0.25
receptor appears to be a successful therapeutic strategy with the
PsA n = 170 (29%) 93 (55) 70 (41) 7 (4) 0.75 0.25
No PsA n = 410 (71%) 235 (57) 151 (37) 24 (6) 0.76 0.24 most rapid efficacy [31–35]. Although there are an increasing
Cw6-positive n = 241 (42%)z 124 (52) 100 (41) 17 (7) 0.72 0.28 number of works investigating the role of different SNPs within
Cw6-negative n = 339 (58%) 204 (60) 121 (36) 14 (4) 0.78 0.22 genes of IL17 family and several conditions, the association
Family history of PsO n = 297 (52%) 160 (54) 117 (39) 20 (7) 0.74 0.26
between SNPs at genes codifying IL17 cytokines or their receptors
No family history of PsO n = 270 (48%) 161 (60) 98 (36) 11 (4) 0.78 0.22
Early onset PsO n = 427 (74%) 233 (55) 172 (40) 22 (5) 0.75 0.25
and PsO has been rarely studied. So far, two reports have shown
Late onset PsO n = 153 (26%) 95 (62) 49 (32) 9 (6) 0.78 0.22 no or weak relation to PsO through association studies. Likewise
to our results, Shibata et al. found no significant allele or genotype
Only significant associations have been marked.
HW = number of patients and controls expected under the Hardy–Weinberg differences in IL17F (rs763780) between 153 Japanese with PsO
equilibrium; MAF: minor allele frequencies; PASI: Psoriasis Area and Severity Index; and 103 healthy controls [24]. Catanoso et al. determined the
PsA: psoriatic arthritis. relationship between SNPs in IL23A, IL23R, IL17A and IL17RA in 118
*
Patients vs. controls (AG + GG vs. AA): OR = 1.33, 95%CI = 1.05–1.69; p = 0.017.
z
Italian patients with PsA and 254 healthy controls, and found no
Cw6-positive vs. Cw6-negative (AG + GG vs. AA): OR = 1.43, 95%CI = 1.02–1.99;
p = 0.037.
significant differences in the allele distribution between the two
groups, although there was weak association between IL17A
rs7747909 and IL17RA rs9606615, rs2241046, rs2241049 and
peripheral PsA [25]. Our PsO study population did not shown
significant association between IL17A rs774909 and PsA, even
Table 4 though subtypes of PsA were not recorded. None of the above
Genotype and minor allele frequencies (MAF) for the IL17F (rs2397084) SNP. studies evaluated the rs4819554 SNP in IL17RA or the rs79877597
Il17F–rs2397084
SNP in IL17E.
In the study herein presented, the IL17RA rs4819554 G allele
TT TC CC T C
was more common in PsO patients with an OR = 1.33 (p = 0.017).
Controls n = 567 (%) 483 (85) 79 (14) 5 (1) 0.92 0.08 The SNP rs4819554 at IL17RA gene was previously linked to the
HW controls 480 83 4
susceptibility or protection to several inflammatory or immuno-
Patients n = 580 (%) 508 (88) 66 (11) 6 (1) 0.93 0.07
HW patients 502 76 3 logical diseases, and also with cancer. The majority of these studies
PASI  10 n = 293 (51%) 259 (88) 29 (10) 5 (2) 0.93 0.07 had taken place in Korean population [18,36–38]. Kim et al.
PASI < 10 n = 287 (49%) 249 (87) 37 (13) 1 (0) 0.93 0.07 observed a relation of A allele of rs4819554 SNP and risk to end-
PsA n = 170 (29%) 151 (89) 18 (10) 1 (1) 0.94 0.06
stage kidney disease. They attribute this effect to differences in
No PsA n = 410 (71%) 357 (87) 49 (12) 4 (1) 0.93 0.07
Cw6-positive n = 241 (42%) 222 (92) 18 (7) 1 (1) 0.96 0.04
binding domains for transcription factors due to changes between
Cw6-negative n = 339 (58%) 288 (85) 47 (14) 4 (1) 0.92 0.08 major and minor alleles at this SNP. These changes may influence
Family history of PsO n = 297 (52%) 267 (90) 30 (10) – 0.95 0.05 the expression of the IL17RA with the subsequent biological effects
No family history of PsO n = 270 (48%) 229 (85) 35 (13) 6 (2) 0.91 0.09 [37]. Recently, the AA genotype of this SNP has been indepen-
Early onset PsO n = 427 (74%) 378 (86) 44 (10) 5 (1) 0.94 0.06
dently associated with a reduced glomerular filtration rate in a
Late onset PsO n = 153 (26%) 130 (85) 22 (14) 1 (1) 0.92 0.08
cohort of Spanish healthy individuals [39]. Another report from
Only significant associations have been shown.
Kim and co-workers found a relation of the SNP rs4819554 and
HW = number of patients and controls expected under the Hardy–Weinberg
equilibrium; MAF: minor allele frequencies; PASI: Psoriasis Area and Severity Index;
higher risk to develop diabetes after renal transplantation. Also in
PsA: psoriatic arthritis. this work, the allele of risk was the A allele [38]. Lew et al. showed
*
Cw6-positive vs. Cw6-negative (TT vs. TC + CC): OR = 2.07; 95%CI = 1.19–3.60; that rs4819554 was related to the age of onset of alopecia areata,
p = 0.010. but not to overall susceptibility [18]. Park et al. reported an

Please cite this article in press as: A. Batalla, et al., Association between single nucleotide polymorphisms IL17RA rs4819554 and IL17E
rs79877597 and Psoriasis in a Spanish cohort., J Dermatol Sci (2015), http://dx.doi.org/10.1016/j.jdermsci.2015.06.011
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Table 5
Genotype and minor allele frequencies (MAF) for the IL17E (rs79877597) SNP.

Il17E–rs79877597

CC AC AA C A
Controls n = 567 (%) 352 (62) 187 (33) 28 (5) 0.79 0.21
HW controls 354 188 25
Patients n = 580 (%) 339 (59) 199 (34) 42 (7) 0.76 0.24
HW patients 335 212 33
PASI  10 n = 293 (51%)* 179 (61) 101 (35) 13 (4) 0.78 0.22
PASI < 10 n = 287 (49%) 160 (56) 98 (34) 29 (10) 0.73 0.27
PsA n = 170 (29%)z 111 (65) 49 (29) 10 (6) 0.80 0.20
No PsA n = 410 (71%) 228 (55) 150 (37) 32 (8) 0.74 0.26
Cw6-positive n = 241 (42%) 133 (55) 91 (38) 17 (7) 0.74 0.26
Cw6-negative n = 339 (58%) 206 (61) 108 (32) 25 (7) 0.77 0.23
Family history of PsO n = 297 (52%) 175 (59) 104 (35) 18 (6) 0.76 0.24
No family history of PsO n = 270 (48%) 157 (58) 89 (33) 24 (9) 0.75 0.25
Early onset PsO n = 427 (74%) 249 (58) 145 (34) 33 (8) 0.75 0.25
Late onset PsO n = 153 (26%) 90 (59) 54 (35) 9 (6) 0.76 0.24

Only significant associations have been shown.

HW = number of patients and controls expected under the Hardy–Weinberg equilibrium; MAF: minor allele frequencies; PASI: Psoriasis Area and Severity Index; PsA:
psoriatic arthritis.
*
PASI  10 vs. PASI < 10 (CC + AC vs. AA): OR = 2.42, 95%CI = 1.23–4.76; p = 0.010.
z
PsA vs. No-PsA (CC vs. AA + AC): OR = 1.50, 95%CI = 1.04–2.18; p = 0.032.

association between three SNPs of the IL17RA gene and aspirin
exacerbated respiratory disease (AERD). Genotype AA in
rs4819553, AA in rs4819554, and GG in rs917864 conferred an
increase risk to AERD. In addition, a synergetic effect was found if
two or three risk genotypes were present. The risk genotype also
correlated with a higher expression of the protein IL17RA on the
surface of monocytes and higher expression of IL17RA mRNA,
which led again to hypothesize that these genotypes exert their
effects acting on promoter domains as inductors or inhibitors of
the transcription [36]. Finally, Lee et al. reported that G allele of
rs4819554 was significantly associated with protection to papil-
lary thyroid cancer. These authors confirmed functional con-
sequences of this genetic variation which caused different
transcription factor sequences depending on the presence of the
G or A allele [40]. Unlike the above mentioned reports, we have
found that the rs4819554 risk allele in our PsO patients was the G
allele. This finding might be explained by differences in genetic
susceptibility in distinct diseases, and by differences in inheritance
models in dissimilar geographic areas or environmental factors
that could result in a protective or risk effect of the same SNP
[20,41,42].
Furthermore, we found a significantly higher frequency of
IL17RA rs4819554 G-carriers in the Cw6-positive subgroup (OR =
1.43; p = 0.037). IL17RA rs879557 T allele (statistical trend) and
IL17F rs2397084 TT genotype (OR = 2.07; p = 0.010) were also more
common in Cw6-positive PsO patients, although both SNPs do not
increase the overall risk to PsO. Due to the known and strong
relation of Cw6-positivity and early onset PsO (also found in our
study, p  0.0001), we applied logistic regression tests to the
associations found between HLA-Cw6 and IL17RA rs4819554 and
IL17F rs2397084, considering the age of onset as the confounding
factor. While the association between rs4819554 and HLA-Cw6 lost
significance (p  0.05), the association between the presence of
HLA-Cw6 and rs2397084 SNP, remained being significant. These
observations could support the role of IL17RA rs4819554 on PsO
risk, independently from HLA-Cw6, and a probably weaker role of
IL17F rs2397084, as this SNP seems to act in combination with HLA-
Cw6. The difference in genotype frequencies between Cw6-
positive and negative patients has been reported for other PsO-
risk candidate polymorphisms. Among others, HLA-Cw6 would
interact with variants at the ERAP1, LCE and IL12B genes to increase
the risk for PsO, and epistasis among these genes have been
described [43–46].
Concerning IL17E rs79877597 SNP, no studies which aimed at
this polymorphism have been reported.
Finally, we are well aware that our study was based on a limited
number of cases and controls. In addition, it was based on patients
and controls from a single population, and replication with larger
cohorts from other populations is required. Studies to link the
positive allele associations to a functional effect (differences in
gene expression and function) are also of special interest.
In conclusion, we report an association between IL17RA
rs4819554 SNP and the risk for PsO, and an association of the
IL17E rs79877597 SNP with more severe forms of PsO and presence
of PsA. Our results needs to be validated in other cohorts, and
studies to determine the effect of this polymorphism of risk on
gene expression should be also required.
Conflict of interest
P. Coto-Segura is an invited speaker for and receives grant/
research support from Abbvie, Janssen-Cilag, Schering-Plough,
Pfizer, Celgene and Novartis. The author have no other relevant
affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript apart from
those disclosed. No writing assistance was utilized in the
production of this manuscript. Other authors declare no conflict
of interest.
IRB status
Our project was approved by the Ethical Committee of HUCA
and also the project has passed the evaluation by the Ethical
Committees belonging to the Scientific Investigative Area of the
Ministry of Health. These material have been uploaded through the
submission online system (within the section of IRB form). This
study does not require IRB approval, as all data were collected in a
retrospective way.
Funding sources
This work was supported by a grant from the Spanish Instituto
de Salud Carlos III-European FEDER founds (grant PI 13/00680).
Authors thank Novartis for supporting this work. Authors thank
Astucor for their suport.

Please cite this article in press as: A. Batalla, et al., Association between single nucleotide polymorphisms IL17RA rs4819554 and IL17E
rs79877597 and Psoriasis in a Spanish cohort., J Dermatol Sci (2015), http://dx.doi.org/10.1016/j.jdermsci.2015.06.011
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Acknowledgement
We thank Belén Alonso for technical assistance.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
jdermsci.2015.06.011.
References
[1] G.K. Perera, P. Di Meglio, F.O. Nestle, Psoriasis, Annu. Rev. Pathol. 7 (2012) 385–
422.
[2] C.E. Griffiths, J.N. Barker, Pathogenesis and clinical features of psoriasis, Lancet
370 (2007) 263–271.
[3] E. Coto, J. Santos-Juanes, P. Coto-Segura, V. Alvarez, New psoriasis
susceptibility genes: momentum for skin-barrier disruption, J. Invest.
Dermatol. 131 (2011) 1003–1005.
[4] R.P. Nair, P.E. Stuart, I. Nistor, R. Hiremagalore, N.V. Chia, S. Jenisch, et al.,
Sequence and haplotype analysis supports HLA-C as the psoriasis
susceptibility 1 gene, Am. J. Hum. Genet. 78 (2006) 827–851.
[5] L. Puig, A. Julia, S. Marsal, The Pathogenesis and Genetics of Psoriasis, Actas
Dermosifiliogr. 105 (2014) 535–545.
[6] C. Gu, L. Wu, X. Li, IL-17 family: cytokines, receptors and signaling, Cytokine 64
(2013) 477–485.
[7] T. Starnes, M.J. Robertson, G. Sledge, S. Kelich, H. Nakshatri, H.E. Broxmeyer,
et al., Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T
cells and monocytes, regulates angiogenesis and endothelial cell cytokine
production, J. Immunol. 167 (2001) 4137–4140.
[8] T. Arisawa, T. Tahara, T. Shibata, M. Nagasaka, M. Nakamura, Y. Kamiya, et al.,
The influence of polymorphisms of interleukin-17A and interleukin-17F genes
on the susceptibility to ulcerative colitis, J. Clin. Immunol. 28 (2008) 44–49.
[9] M. Kawaguchi, M. Adachi, N. Oda, F. Kokubu, S.K. Huang, IL-17 cytokine family,
J. Allergy. Clin. Immunol. 114 (2004) 1265–1273.
[10] N.J. Wilson, K. Boniface, J.R. Chan, B.S. McKenzie, W.M. Blumenschein, J.D.
Mattson, et al., Development, cytokine profile and function of human
interleukin 1producing helper T cells, Nat. Immunol. 8 (2007) 950–957.
[11] S. Kagami, H.L. Rizzo, J.J. Lee, Y. Koguchi, A. Blauvelt, Circulating Th17, Th22, and
Th1 cells are increased in psoriasis, J. Invest. Dermatol. 130 (2010) 1373–1383.
[12] E.G. Harper, C. Guo, H. Rizzo, J.V. Lillis, S.E. Kurtz, I. Skorcheva, et al., Th17
cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo:
implications for psoriasis pathogenesis, J. Invest. Dermatol. 129 (2009) 2175–
2183.
[13] T. Korn, E. Bettelli, M. Oukka, V.K. Kuchroo, IL-17 and Th17Cells, Annu. Rev.
Immunol. 27 (2009) 485–517.
[14] K. Pukelsheim, T. Stoeger, D. Kutschke, K. Ganguly, M. Wjst, Cytokine profiles in
asthma families depend on age and phenotype, Plos One 5 (2010) 14299.
[15] S.L. Gaffen, Structure and signalling in the IL-17 receptor family, Nat. Rev.
Immunol. 9 (2009) 556–567.
[16] N. Yan, Y.L. Yu, J. Yang, Q. Qin, Y.F. Zhu, X. Wang, et al., Association of
interleukin-17A and -17F gene single-nucleotide polymorphisms with
autoimmune thyroid diseases, Autoimmunity 45 (2012) 533–539.
[17] W.C. Jang, Y.H. Nam, Y.C. Ahn, S.H. Lee, S.H. Park, J.Y. Choe, et al., Interleukin-17F
gene polymorphisms in Korean patients with Behcet’s disease, Rheumatol. Int.
29 (2008) 173–178.
[18] B.L. Lew, H.R. Cho, S. Haw, H.J. Kim, J.H. Chung, W.Y. Sim, Association between
IL17A/IL17RA Gene Polymorphisms and Susceptibility to Alopecia Areata in the
Korean Population, Ann. Dermatol. 24 (2012) 61–65.
[19] J.D. Correa, M.F. Madeira, R.G. Resende, F. Correia-Silva Jde, R.S. Gomez, G. de
Souza Dda, et al., Association between polymorphisms in interleukin-17A and
-17F genes and chronic periodontal disease, Mediators Inflamm. 2012 (2012)
846052.
[20] R. Peng, J. Yue, M. Han, Y. Zhao, L. Liu, L. Liang, The IL-17F sequence variant is
associated with susceptibility to tuberculosis, Gene 515 (2013) 229–232.
[21] V.S. Chaitanya, R.S. Jadhav, M. Lavania, M. Singh, V. Valluri, U. Sengupta,
Interleukin-17F single-nucleotide polymorphism (7488T > C) and its
association with susceptibility to leprosy, Int. J. Immunogenet. 41 (2014) 101–
107.
[22] W. Dai, Q. Zhou, X. Tan, C. Sun, IL-17A (-197G/A) and IL-17F (7488T/C) gene
polymorphisms and cancer risk in Asian population: a meta-analysis, Onco.
Targets Ther. 7 (2014) 703–711.
Please cite this article in press as: A. Batalla, et al., Association between single nucleotide polymorphisms IL17RA rs4819554 and IL17E
rs79877597 and Psoriasis in a Spanish cohort., J Dermatol Sci (2015), http://dx.doi.org/10.1016/j.jdermsci.2015.06.011
5
[23] B. Zhou, P. Zhang, Y. Wang, S. Shi, K. Zhang, H. Liao, et al., Interleukin-17 gene
polymorphisms are associated with bladder cancer in a Chinese Han
population, Mol. Carcinog. 52 (2013) 871–878.
[24] S. Shibata, H. Saeki, Y. Tsunemi, T. Kato, K. Nakamura, T. Kakinuma, et al., IL -17F
single nucleotide polymorphism is not associated with psoriasis vulgaris or
atopic dermatitis in the Japanese population, J. Dermatol. Sci. (2009) 163–165.
[25] M.G. Catanoso, L. Boiardi, P. Macchioni, P. Garagnani, M. Sazzini, S. De Fanti,
et al., IL-23A, IL-23R, IL-17A and IL-17R polymorphisms in different psoriatic
arthritis clinical manifestations in the northern Italian population, Rheumatol.
Int. 33 (2013) 1165–1176.
[26] W. Taylor, D. Gladman, P. Helliwell, A. Marchesoni, P. Mease, H. Mielants,
Classification criteria for psoriatic arthritis: development of new criteria from
a large international study, Arthritis Rheum. 54 (2006) 2665–2673.
[27] L. Gonzalez-Lara, P. Coto-Segura, A. Penedo, N. Eiris, M. Diaz, J. Santos-Juanes,
et al., SNP rs11652075 in the CARD1gene as a risk factor for psoriasis (PSORS2)
in a Spanish cohort, DNA Cell Biol. 32 (2013) 601–604.
[28] W.J. Wang, X.Y. Yin, X.B. Zuo, H. Cheng, W.D. Du, F.Y. Zhang, et al., Gene-gene
interactions in IL23/Th17 pathway contribute to psoriasis susceptibility in
Chinese Han population, J. Eur. Acad. Dermatol. Venereol. 27 (2013) 1156–1162.
[29] M. Cargill, S.J. Schrodi, M. Chang, V.E. Garcia, R. Brandon, K.P. Callis, et al., A
large-scale genetic association study confirms IL12B and leads to the
identification of IL23R as psoriasis-risk genes, Am. J. Hum. Genet. 80 (2007)
273–290.
[30] E. Ellinghaus, D. Ellinghaus, P.E. Stuart, R.P. Nair, S. Debrus, J.V. Raelson, et al.,
Genome-wide association study identifies a psoriasis susceptibility locus at
TRAF3IP2, Nat. Genet. 42 (2010) 991–995.
[31] A. Chiricozzi, J.G. Krueger, IL-17 targeted therapies for psoriasis, Expert Opin.
Invest. Drugs 22 (2013) 993–1005.
[32] Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al.
Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque
[33] K.A. Papp, C. Leonardi, A. Menter, J.P. Ortonne, J.G. Krueger, G. Kricorian, et al.,
Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis, N. Engl. J.
Med. 366 (2012) 1181–1189.
[34] K.A. Papp, C. Reid, P. Foley, R. Sinclair, D.H. Salinger, G. Williams, et al., Anti-IL-
17 receptor antibody AMG 827 leads to rapid clinical response in subjects with
moderate to severe psoriasis: results from a phase I, randomized, placebo-
controlled trial, J. Invest. Dermatol. 132 (2012) 2466–2469.
[35] K.A. Papp, R.G. Langley, B. Sigurgeirsson, M. Abe, D.R. Baker, P. Konno, et al.,
Efficacy and safety of secukinumab in the treatment of moderate-to-severe
plaque psoriasis: a randomized, double-blind, placebo-controlled phase II
dose-ranging study, Br. J. Dermatol. 168 (2013) 412–421.
[36] J.S. Park, B.L. Park, M.O. Kim, J.S. Heo, J.S. Jung, D.J. Bae, et al., Association of
single nucleotide polymorphisms on Interleukin 17 receptor A (IL17RA) gene
with aspirin hypersensitivity in asthmatics, Hum. Immunol. 74 (2013) 598–
606.
[37] Y.G. Kim, E.Y. Kim, C.G. Ihm, T.W. Lee, S.H. Lee, K.H. Jeong, et al., Gene
polymorphisms of interleukin-1and interleukin-1receptor are associated with
end-stage kidney disease, Am. J. Nephrol. 36 (2012) 472–477.
[38] Y.G. Kim, C.G. Ihm, T.W. Lee, S.H. Lee, K.H. Jeong, J.Y. Moon, et al., Association of
genetic polymorphisms of interleukins with new-onset diabetes after
transplantation in renal transplantation, Transplantation 93 (2012) 900–907.
[39] E. Coto, J. Gomez, B. Suarez, S. Tranche, C. Diaz-Corte, A. Ortiz, et al., Association
between the IL17RA rs4819554 polymorphism and reduced renal filtration rate
in the Spanish RENASTUR cohort, Hum. Immunol. (2015) (Epub).
[40] Y.C. Lee, J.H. Chung, S.K. Kim, S.Y. Rhee, S. Chon, S.J. Oh, et al., Association
between interleukin 17/interleukin 17 receptor gene polymorphisms and
papillary thyroid cancer in Korean population, Cytokine 71 (2015) 283–288.
[41] S.M. Kariuki, K. Rockett, T.G. Clark, H. Reyburn, T. Agbenyega, T.E. Taylor, et al.,
The genetic risk of acute seizures in African children with falciparum malaria,
Epilepsia 54 (2013) 990–1001.
[42] A.M. Saraiva, M.R. Alves e Silva, F. Correia Silva Jde, J.E. da Costa, K.J. Gollob, W.
O. Dutra, et al., Evaluation of IL17A expression and of IL17A, IL17F and IL23R
gene polymorphisms in Brazilian individuals with periodontitis, Hum.
Immunol. 74 (2013) 207–214.
[43] A. Strange, F. Capon, C.C. Spencer, J. Knight, M.E. Weale, M.H. Allen, et al., A
genome-wide association study identifies new psoriasis susceptibility loci and
an interaction between HLA-C and ERAP1, Nat. Genet. 42 (2010) 985–990.
[44] H.F. Zheng, X.B. Zuo, W.S. Lu, Y. Li, H. Cheng, K.J. Zhu, et al., Variants in MHC, LCE
and IL12B have epistatic effects on psoriasis risk in Chinese population, J.
Dermatol. Sci. 61 (2011) 124–128.
[45] E. Riveira-Munoz, S.M. He, G. Escaramis, P.E. Stuart, U. Huffmeier, C. Lee, et al.,
Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis
in several ethnic groups and finds interaction with HLA-Cw6, J. Invest.
Dermatol. 131 (2011) 1105–1109.
[46] R. de Cid, E. Riveira-Munoz, P.L. Zeeuwen, J. Robarge, W. Liao, E.N. Dannhauser,
et al., Deletion of the late cornified envelope LCE3B and LCE3C genes as a
susceptibility factor for psoriasis, Nat. Genet. 41 (2009) 211–215.