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Association between single nucleotide polymorphisms IL17RA rs4819554 and IL17E rs79877597 and Psoriasis in a Spanish cohort.
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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 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 b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 February 2015 Received in revised form 29 April 2015 Accepted 23 June 2015
Background: The IL17 pathway plays an important role in the pathogenesis of psoriasis (PsO). Objectives: To determine whether the variation at the IL17 pathway genes was linked to the risk for PsO or had an effect on disease severity and the risk for Psoriatic arthritis (PsA). 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), IL17A (rs7747909), IL17F (rs763780, rs2397084), and IL17E (rs79877597) genes. Results: We found significant higher frequencies of IL17RA rs4819554 G carriers among the patients (OR = 1.33, 95%CI = 1.05–1.69; p = 0.017). The IL17RA rs4819554 G allele and IL17F rs2397084 TT genotype were significantly more frequent among Cw6 positive patients (p = 0.037 and p = 0.010, respectively). The IL17E rs79877597C allele was significantly more common among patients with severe forms of PsO (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.
Keywords: Gene polymorphism Genetic susceptibility Genotypes IL17 pathway genes Psoriasis Psoriatic arthritis
1. Introduction 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 background 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: [email protected] (P. Coto-Segura).
to this well characterized genetic association, other immunological 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 IL17RA and respond to IL-17A and IL-17F producing, among others, IL6, 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 polymorphisms (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 nonsevere 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) Age (years) (mean SD) HLA-Cw6 presence Family history of psoriasis* Early onset psoriasisz
Late onset psoriasisz
Mild–to–moderate psoriasis Severe psoriasis# Arthritis
#
313 (54%)/267 (46%) 47.09 14.66 241 (42%) 297 (52%) 427 (74%) Age (median) HLA_Cw6 presence 153 (26%) Age (median) HLA_Cw6 presence 287 (49%) 293 (51%) 170 (29%)
19 208 (49%) 52 33 (22%)
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.
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 frequencies 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 nonsignificant 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 Cw6positive 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 rs2397084, did not differ between patients according to disease severity, presence of PsA, or other demographic or clinical characteristics (Tables 3–4, Table A.3.) 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
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 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 (%) Patients n = 580 (%) PASI 10 n = 293 (51%) PASI < 10 n = 287 (49%) PsA n = 170 (29%) No PsA n = 410 (71%) Cw6-positive n = 241(42%) Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
0.20 0.24 0.24 0.25 0.25 0.24 0.28 0.22 0.26 0.22 0.25 0.22
0.23 0.25 0.26 0.24 0.26 0.24 0.28 0.23 0.25 0.24 0.25 0.22
0.25 0.27 0.26 0.28 0.26 0.27 0.27 0.27 0.27 0.27 0.28 0.25
Table 3 Genotype and minor allele frequencies (MAF) for the Il17RA (rs4819554) SNP.
AA
AG
GG
A
G
360 (63) 363 328 (57) 335 166 (57) 162 (56) 93 (55) 235 (57) 124 (52) 204 (60) 160 (54) 161 (60) 233 (55) 95 (62)
187 (33) 181 221 (38) 212 112 (38) 109 (38) 70 (41) 151 (37) 100 (41) 121 (36) 117 (39) 98 (36) 172 (40) 49 (32)
20 (4) 23 31 (5) 33 15 (5) 16 (6) 7 (4) 24 (6) 17 (7) 14 (4) 20 (7) 11 (4) 22 (5) 9 (6)
0.80 0.20 0.76 0.24 0.76 0.75 0.75 0.76 0.72 0.78 0.74 0.78 0.75 0.78
0.24 0.25 0.25 0.24 0.28 0.22 0.26 0.22 0.25 0.22
Only significant associations have been marked. 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. * Patients vs. controls (AG + GG vs. AA): OR = 1.33, 95%CI = 1.05–1.69; p = 0.017. z Cw6-positive vs. Cw6-negative (AG + GG vs. AA): OR = 1.43, 95%CI = 1.02–1.99; p = 0.037.
Table 4 Genotype and minor allele frequencies (MAF) for the IL17F (rs2397084) SNP. Il17F–rs2397084
Controls n = 567 (%) HW controls Patients n = 580 (%) HW patients PASI 10 n = 293 (51%) PASI < 10 n = 287 (49%) PsA n = 170 (29%) No PsA n = 410 (71%) Cw6-positive n = 241 (42%) Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
0.08 0.07 0.07 0.07 0.06 0.07 0.04 0.08 0.05 0.09 0.06 0.08
0.21 0.24 0.22 0.27 0.20 0.26 0.26 0.23 0.24 0.25 0.25 0.24
significant associations between these SNPs and other demographic or clinical data were detected (Tables A.4–5). 4. Discussion
Il17RA-rs4819554
Controls n = 567 (%) HW controls Patients n = 580 (%)* HW patients PASI 10 n = 293 (51%) PASI < 10 n = 287 (49%) PsA n = 170 (29%) No PsA n = 410 (71%) Cw6-positive n = 241 (42%)z Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
0.06 0.05 0.05 0.05 0.06 0.05 0.04 0.06 0.05 0.06 0.05 0.07
TT
TC
CC
483 (85) 480 508 (88) 502 259 (88) 249 (87) 151 (89) 357 (87) 222 (92) 288 (85) 267 (90) 229 (85) 378 (86) 130 (85)
79 (14) 83 66 (11) 76 29 (10) 37 (13) 18 (10) 49 (12) 18 (7) 47 (14) 30 (10) 35 (13) 44 (10) 22 (14)
5 4 6 3 5 1 1 4 1 4 – 6 5 1
T
C
(1) 0.92
0.08
(1) 0.93
0.07
(2) (0) (1) (1) (1) (1)
0.07 0.07 0.06 0.07 0.04 0.08 0.05 0.09 0.06 0.08
0.93 0.93 0.94 0.93 0.96 0.92 0.95 (2) 0.91 (1) 0.94 (1) 0.92
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. * Cw6-positive vs. Cw6-negative (TT vs. TC + CC): OR = 2.07; 95%CI = 1.19–3.60; p = 0.010.
The current pathogenic model of PsO emphasizes the IL-23/ IL17 axis.[28] Genome wide association studies (GWAS) have linked PsO-risk to SNPs at the IL-23R and ACT1, two regulators of IL-17 production and IL-17-mediated signaling [29,30]. In addition, a new subset of anti-psoriatic agents against IL-17 or its receptor appears to be a successful therapeutic strategy with the most rapid efficacy [31–35]. Although there are an increasing number of works investigating the role of different SNPs within genes of IL17 family and several conditions, the association between SNPs at genes codifying IL17 cytokines or their receptors and PsO has been rarely studied. So far, two reports have shown no or weak relation to PsO through association studies. Likewise to our results, Shibata et al. found no significant allele or genotype differences in IL17F (rs763780) between 153 Japanese with PsO and 103 healthy controls [24]. Catanoso et al. determined the relationship between SNPs in IL23A, IL23R, IL17A and IL17RA in 118 Italian patients with PsA and 254 healthy controls, and found no 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 though subtypes of PsA were not recorded. None of the above studies evaluated the rs4819554 SNP in IL17RA or the rs79877597 SNP in IL17E. In the study herein presented, the IL17RA rs4819554 G allele was more common in PsO patients with an OR = 1.33 (p = 0.017). The SNP rs4819554 at IL17RA gene was previously linked to the susceptibility or protection to several inflammatory or immunological diseases, and also with cancer. The majority of these studies had taken place in Korean population [18,36–38]. Kim et al. observed a relation of A allele of rs4819554 SNP and risk to endstage kidney disease. They attribute this effect to differences in binding domains for transcription factors due to changes between major and minor alleles at this SNP. These changes may influence the expression of the IL17RA with the subsequent biological effects [37]. Recently, the AA genotype of this SNP has been independently associated with a reduced glomerular filtration rate in a cohort of Spanish healthy individuals [39]. Another report from Kim and co-workers found a relation of the SNP rs4819554 and higher risk to develop diabetes after renal transplantation. Also in this work, the allele of risk was the A allele [38]. Lew et al. showed that rs4819554 was related to the age of onset of alopecia areata, 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
Controls n = 567 (%) HW controls Patients n = 580 (%) HW patients PASI 10 n = 293 (51%)* PASI < 10 n = 287 (49%) PsA n = 170 (29%)z No PsA n = 410 (71%) Cw6-positive n = 241 (42%) Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
CC
AC
AA
C
A
352 (62) 354 339 (59) 335 179 (61) 160 (56) 111 (65) 228 (55) 133 (55) 206 (61) 175 (59) 157 (58) 249 (58) 90 (59)
187 (33) 188 199 (34) 212 101 (35) 98 (34) 49 (29) 150 (37) 91 (38) 108 (32) 104 (35) 89 (33) 145 (34) 54 (35)
28 (5) 25 42 (7) 33 13 (4) 29 (10) 10 (6) 32 (8) 17 (7) 25 (7) 18 (6) 24 (9) 33 (8) 9 (6)
0.79
0.21
0.76
0.24
0.78 0.73 0.80 0.74 0.74 0.77 0.76 0.75 0.75 0.76
0.22 0.27 0.20 0.26 0.26 0.23 0.24 0.25 0.25 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 papillary thyroid cancer. These authors confirmed functional consequences 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 HLACw6. The difference in genotype frequencies between Cw6positive and negative patients has been reported for other PsOrisk 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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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
Journal of Dermatological Science xxx (2015) xxx–xxx
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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 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 b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 February 2015 Received in revised form 29 April 2015 Accepted 23 June 2015
Background: The IL17 pathway plays an important role in the pathogenesis of psoriasis (PsO). Objectives: To determine whether the variation at the IL17 pathway genes was linked to the risk for PsO or had an effect on disease severity and the risk for Psoriatic arthritis (PsA). 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), IL17A (rs7747909), IL17F (rs763780, rs2397084), and IL17E (rs79877597) genes. Results: We found significant higher frequencies of IL17RA rs4819554 G carriers among the patients (OR = 1.33, 95%CI = 1.05–1.69; p = 0.017). The IL17RA rs4819554 G allele and IL17F rs2397084 TT genotype were significantly more frequent among Cw6 positive patients (p = 0.037 and p = 0.010, respectively). The IL17E rs79877597C allele was significantly more common among patients with severe forms of PsO (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.
Keywords: Gene polymorphism Genetic susceptibility Genotypes IL17 pathway genes Psoriasis Psoriatic arthritis
1. Introduction 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 background 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: [email protected] (P. Coto-Segura).
to this well characterized genetic association, other immunological 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 IL17RA and respond to IL-17A and IL-17F producing, among others, IL6, 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 polymorphisms (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 nonsevere 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) Age (years) (mean SD) HLA-Cw6 presence Family history of psoriasis* Early onset psoriasisz
Late onset psoriasisz
Mild–to–moderate psoriasis Severe psoriasis# Arthritis
#
313 (54%)/267 (46%) 47.09 14.66 241 (42%) 297 (52%) 427 (74%) Age (median) HLA_Cw6 presence 153 (26%) Age (median) HLA_Cw6 presence 287 (49%) 293 (51%) 170 (29%)
19 208 (49%) 52 33 (22%)
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.
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 frequencies 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 nonsignificant 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 Cw6positive 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 rs2397084, did not differ between patients according to disease severity, presence of PsA, or other demographic or clinical characteristics (Tables 3–4, Table A.3.) 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
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 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 (%) Patients n = 580 (%) PASI 10 n = 293 (51%) PASI < 10 n = 287 (49%) PsA n = 170 (29%) No PsA n = 410 (71%) Cw6-positive n = 241(42%) Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
0.20 0.24 0.24 0.25 0.25 0.24 0.28 0.22 0.26 0.22 0.25 0.22
0.23 0.25 0.26 0.24 0.26 0.24 0.28 0.23 0.25 0.24 0.25 0.22
0.25 0.27 0.26 0.28 0.26 0.27 0.27 0.27 0.27 0.27 0.28 0.25
Table 3 Genotype and minor allele frequencies (MAF) for the Il17RA (rs4819554) SNP.
AA
AG
GG
A
G
360 (63) 363 328 (57) 335 166 (57) 162 (56) 93 (55) 235 (57) 124 (52) 204 (60) 160 (54) 161 (60) 233 (55) 95 (62)
187 (33) 181 221 (38) 212 112 (38) 109 (38) 70 (41) 151 (37) 100 (41) 121 (36) 117 (39) 98 (36) 172 (40) 49 (32)
20 (4) 23 31 (5) 33 15 (5) 16 (6) 7 (4) 24 (6) 17 (7) 14 (4) 20 (7) 11 (4) 22 (5) 9 (6)
0.80 0.20 0.76 0.24 0.76 0.75 0.75 0.76 0.72 0.78 0.74 0.78 0.75 0.78
0.24 0.25 0.25 0.24 0.28 0.22 0.26 0.22 0.25 0.22
Only significant associations have been marked. 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. * Patients vs. controls (AG + GG vs. AA): OR = 1.33, 95%CI = 1.05–1.69; p = 0.017. z Cw6-positive vs. Cw6-negative (AG + GG vs. AA): OR = 1.43, 95%CI = 1.02–1.99; p = 0.037.
Table 4 Genotype and minor allele frequencies (MAF) for the IL17F (rs2397084) SNP. Il17F–rs2397084
Controls n = 567 (%) HW controls Patients n = 580 (%) HW patients PASI 10 n = 293 (51%) PASI < 10 n = 287 (49%) PsA n = 170 (29%) No PsA n = 410 (71%) Cw6-positive n = 241 (42%) Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
0.08 0.07 0.07 0.07 0.06 0.07 0.04 0.08 0.05 0.09 0.06 0.08
0.21 0.24 0.22 0.27 0.20 0.26 0.26 0.23 0.24 0.25 0.25 0.24
significant associations between these SNPs and other demographic or clinical data were detected (Tables A.4–5). 4. Discussion
Il17RA-rs4819554
Controls n = 567 (%) HW controls Patients n = 580 (%)* HW patients PASI 10 n = 293 (51%) PASI < 10 n = 287 (49%) PsA n = 170 (29%) No PsA n = 410 (71%) Cw6-positive n = 241 (42%)z Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
0.06 0.05 0.05 0.05 0.06 0.05 0.04 0.06 0.05 0.06 0.05 0.07
TT
TC
CC
483 (85) 480 508 (88) 502 259 (88) 249 (87) 151 (89) 357 (87) 222 (92) 288 (85) 267 (90) 229 (85) 378 (86) 130 (85)
79 (14) 83 66 (11) 76 29 (10) 37 (13) 18 (10) 49 (12) 18 (7) 47 (14) 30 (10) 35 (13) 44 (10) 22 (14)
5 4 6 3 5 1 1 4 1 4 – 6 5 1
T
C
(1) 0.92
0.08
(1) 0.93
0.07
(2) (0) (1) (1) (1) (1)
0.07 0.07 0.06 0.07 0.04 0.08 0.05 0.09 0.06 0.08
0.93 0.93 0.94 0.93 0.96 0.92 0.95 (2) 0.91 (1) 0.94 (1) 0.92
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. * Cw6-positive vs. Cw6-negative (TT vs. TC + CC): OR = 2.07; 95%CI = 1.19–3.60; p = 0.010.
The current pathogenic model of PsO emphasizes the IL-23/ IL17 axis.[28] Genome wide association studies (GWAS) have linked PsO-risk to SNPs at the IL-23R and ACT1, two regulators of IL-17 production and IL-17-mediated signaling [29,30]. In addition, a new subset of anti-psoriatic agents against IL-17 or its receptor appears to be a successful therapeutic strategy with the most rapid efficacy [31–35]. Although there are an increasing number of works investigating the role of different SNPs within genes of IL17 family and several conditions, the association between SNPs at genes codifying IL17 cytokines or their receptors and PsO has been rarely studied. So far, two reports have shown no or weak relation to PsO through association studies. Likewise to our results, Shibata et al. found no significant allele or genotype differences in IL17F (rs763780) between 153 Japanese with PsO and 103 healthy controls [24]. Catanoso et al. determined the relationship between SNPs in IL23A, IL23R, IL17A and IL17RA in 118 Italian patients with PsA and 254 healthy controls, and found no 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 though subtypes of PsA were not recorded. None of the above studies evaluated the rs4819554 SNP in IL17RA or the rs79877597 SNP in IL17E. In the study herein presented, the IL17RA rs4819554 G allele was more common in PsO patients with an OR = 1.33 (p = 0.017). The SNP rs4819554 at IL17RA gene was previously linked to the susceptibility or protection to several inflammatory or immunological diseases, and also with cancer. The majority of these studies had taken place in Korean population [18,36–38]. Kim et al. observed a relation of A allele of rs4819554 SNP and risk to endstage kidney disease. They attribute this effect to differences in binding domains for transcription factors due to changes between major and minor alleles at this SNP. These changes may influence the expression of the IL17RA with the subsequent biological effects [37]. Recently, the AA genotype of this SNP has been independently associated with a reduced glomerular filtration rate in a cohort of Spanish healthy individuals [39]. Another report from Kim and co-workers found a relation of the SNP rs4819554 and higher risk to develop diabetes after renal transplantation. Also in this work, the allele of risk was the A allele [38]. Lew et al. showed that rs4819554 was related to the age of onset of alopecia areata, 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
Controls n = 567 (%) HW controls Patients n = 580 (%) HW patients PASI 10 n = 293 (51%)* PASI < 10 n = 287 (49%) PsA n = 170 (29%)z No PsA n = 410 (71%) Cw6-positive n = 241 (42%) Cw6-negative n = 339 (58%) Family history of PsO n = 297 (52%) No family history of PsO n = 270 (48%) Early onset PsO n = 427 (74%) Late onset PsO n = 153 (26%)
CC
AC
AA
C
A
352 (62) 354 339 (59) 335 179 (61) 160 (56) 111 (65) 228 (55) 133 (55) 206 (61) 175 (59) 157 (58) 249 (58) 90 (59)
187 (33) 188 199 (34) 212 101 (35) 98 (34) 49 (29) 150 (37) 91 (38) 108 (32) 104 (35) 89 (33) 145 (34) 54 (35)
28 (5) 25 42 (7) 33 13 (4) 29 (10) 10 (6) 32 (8) 17 (7) 25 (7) 18 (6) 24 (9) 33 (8) 9 (6)
0.79
0.21
0.76
0.24
0.78 0.73 0.80 0.74 0.74 0.77 0.76 0.75 0.75 0.76
0.22 0.27 0.20 0.26 0.26 0.23 0.24 0.25 0.25 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 papillary thyroid cancer. These authors confirmed functional consequences 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 HLACw6. The difference in genotype frequencies between Cw6positive and negative patients has been reported for other PsOrisk 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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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