Association of Interleukin-2, but not Interferon-Gamma, single nucleotide polymorphisms with juvenile idiopathic arthritis

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"apellidos" => "Rezaei" "email" => array:1 [ 0 => "rezaei_nima@tums.ac.ir" ] "referencia" => array:5 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 2 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] 3 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] 4 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Molecular Immunology Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "IntroductionJuvenile idiopathic arthritis (JIA) is the most prevalent chronic arthritic condition of childhood with its prevalence varying worldwide among different ethnicities,<a class="elsevierStyleCrossRef" href="#bib0175">14</a> which comprises seven distinct categories as demarcated by the International League of Associations for Rheumatology (ILAR) classification criteria.<a class="elsevierStyleCrossRef" href="#bib0185">16</a> JIA encompasses all forms of arthritis of unknown aetiology that commence before the age of 16 years and persists for more than 6 weeks.<a class="elsevierStyleCrossRef" href="#bib0185">16</a> Notwithstanding the heterogeneity between the JIA subgroups, they do appear to have genetic risk factors in common.<a class="elsevierStyleCrossRef" href="#bib0140">7</a> The common feature of all JIA subtypes is the presence of chronic inflammation within synovial joints, in which cytokines play pivotal roles. It has been previously suggested that certain single nucleotide polymorphisms (SNPs) within the promoter and coding sequences of various cytokines’ genes, which affect their level of production, could be associated with the vulnerability to a group of autoimmune disorders.<a class="elsevierStyleCrossRefs" href="#bib0125">4,6,10,12,21</a>In the current study, we have selected two of the cytokines, including interferon-gamma (IFN-γ) and interleukin-2 (IL-2), that have been reported previously to have a role in JIA aetiopathogenesis,<a class="elsevierStyleCrossRefs" href="#bib0120">3,19</a> to determine whether certain SNPs in these cytokines’ genes are associated with susceptibility to JIA.It has been postulated that these genes may also confer susceptibility to JIA. Therefore, the aim of this study was to assess whether IL-2 (G/T at −330 and +166) as well as IFN-γ (A/T at +874) gene polymorphisms are also associated with susceptibility to JIA in Iranian patients.Patients and methodsStudy populationA total of 54 consecutive JIA patients, recruited from the Rheumatology Clinic of the Children's Medical Center Hospital, the Paediatrics Center of Excellence in Iran, were included in the case group and compared to 139 healthy unrelated individuals who were randomly selected from blood donors at Iranian blood transfusion organisations.<a class="elsevierStyleCrossRef" href="#bib0110">1</a> Diagnosis of JIA was based on the ILAR classification criteria for JIA.<a class="elsevierStyleCrossRef" href="#bib0190">17</a> Our patients’ group comprised 24 individuals with oligoarticular JIA, 19 with polyarticular JIA, and 11 with systemic disease subtype.Written informed consents were obtained from all entrants to this investigation, and the study protocol was approved by the Ethical Committee of Tehran University of Medical Sciences.Sampling and genotypingTo obtain genomic DNA, 5mL of peripheral blood was collected from each patient and stored at −20°C in EDTA tubes until DNA extraction using the “salting out” technique.<a class="elsevierStyleCrossRef" href="#bib0170">13</a> Polymerase chain reaction, with sequence-specific primers method (PCR-SSP assay kit; Heidelberg University, Germany) was employed for cytokine gene typing according to the manufacturer's instructions.<a class="elsevierStyleCrossRef" href="#bib0110">1</a> The three single nucleotide polymorphisms (SNPs) studied were IL-2 (G/T at −330 and +166) and IFN-γ (A/T at +874).Statistical analysisThe allele, genotype and haplotype frequencies were evaluated by direct gene counting and compared with the healthy controls using the chi square test. The odds ratio (OR) and 95% confidence interval (CI) were estimated for each allele, genotype, and haplotype in the patient and control groups. Adherence to the Hardy–Weinberg equilibrium for each genotype was assessed for both case and control groups using the chi square test. P values of less than 0.05 were considered statistically significant.ResultsAllele, genotype and haplotype frequenciesThe allelic and genotype frequencies in patients with JIA and healthy controls are demonstrated in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>A positive genotypic association was detected for IL-2 −330/GG with JIA susceptibility (28.8% vs. 5.8%, p<0.01). Meanwhile, the GT genotype frequency at IL-2 −330 in JIA patient was notably lower than in healthy individuals (33.3% vs. 67.6%, p<0.01). No significant difference was discovered between the two groups of case and control for IL-2 (G/T at +166) and IFN-γ (A/T at +874) SNPs.At the haplotypic level, IL-2 (−330, +166) GT haplotype was found to be more frequent in patients with JIA in comparison with healthy controls (3.6% vs. 0.3%, p=0.04). We observed no significant differences between the two groups for GG, TG and TT haplotypes at the same positions (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>In addition, no significant difference was detected between the aforementioned gene polymorphisms and individuals’ susceptibility to different JIA subtypes, including systemic, polyarticular, and oligoarticular JIA.DiscussionThis study aims at evaluating the association of IL-2 (−330 G/T, +166 G/T) and IFN-γ (+874 A/T) single nucleotide polymorphisms in Iranian patients with JIA. To the best of our knowledge, ours is the first study to analyse the role of the above-said gene variants in susceptibility to JIA in an Iranian population.Interleukin-2 (IL-2) is recognised as a typical T helper 1 (Th1) cytokine, which exerts forceful modulatory effect on various immune cells.<a class="elsevierStyleCrossRef" href="#bib0160">11</a> It has been proposed that dysfunction of the IL-2 could culminate in functional or pathological alterations in the immune system, resulting in autoimmunity.<a class="elsevierStyleCrossRef" href="#bib0145">8</a> It is widely accepted that IL-2 expression is reduced in peripheral blood and both the synovial fluid and the synovium of patients with rheumatoid arthritis (RA) compared to healthy individuals.<a class="elsevierStyleCrossRefs" href="#bib0160">11,20</a> Furthermore, IL-2 protein has previously been identified to be decreased in the sera of patients with systemic-onset JIA.<a class="elsevierStyleCrossRef" href="#bib0200">19</a>IL-2 SNPs are the probable underlying causes of the variations found in IL-2 concentrations between patients and controls.<a class="elsevierStyleCrossRef" href="#bib0160">11</a> Two single nucleotide polymorphisms have been recognised at −330 G/T and +166 G/T positions from the transcription start site in IL-2 gene.<a class="elsevierStyleCrossRef" href="#bib0150">9</a> The allele G at IL-2 −330 position is known to be associated with higher levels of IL-2 production.<a class="elsevierStyleCrossRef" href="#bib0110">1</a> In the present study, we found overrepresentation of the GG genotype (acknowledged as a polymorphism with an elevated level of IL-2 secretion<a class="elsevierStyleCrossRef" href="#bib0110">1</a>) at IL-2 −330 position in the patients group, whilst the frequency of the GT genotype at the same position (identified as a genotype with an intermediate level of cytokine gene expression<a class="elsevierStyleCrossRef" href="#bib0110">1</a>) was found to be lower than the controls. Moreover, at the haplotype level, we detected GT haplotype at IL-2 (−330, +166) to be more frequent in patients with JIA compared to healthy individuals. Our findings are in line with the results of the association study carried out by Pawlik et al., which revealed the association of IL-2 −330 GG genotype with RA severity.<a class="elsevierStyleCrossRef" href="#bib0180">15</a>Interferon-gamma (IFN-γ), a pleiotropic cytokine with antiviral properties, is another Th1 cytokine, which affects inflammation through promoting macrophages to secrete inflammatory and tissue-damaging mediators, including proteases, reactive oxygen species, nitric oxide and tumour necrosis factor alpha (TNF-α), as well as enhancing major histocompatibility complex (MHC) class II expression.<a class="elsevierStyleCrossRef" href="#bib0130">5</a> This cytokine is found in the synovial tissue and in the fluid of RA patients.<a class="elsevierStyleCrossRef" href="#bib0115">2</a> In addition, changes in the levels of IFN-γ protein have been previously reported in the sera of patients with systemic-onset JIA.<a class="elsevierStyleCrossRef" href="#bib0160">11</a> As the IFN-γ gene polymorphisms may be the plausible candidates for individuals’ proneness to JIA, the functional SNP at IFN-γ +874 position, which maps to a putative nuclear factor-kB (NF-kB) binding site, has been analysed in the current study. The presence of T allele at the afore-mentioned position enhances the NF-kB binding efficiency resulting in elevated IFN-γ production.<a class="elsevierStyleCrossRef" href="#bib0195">18</a> In the present study, we did not detect any association between SNPs at IFN-γ +874 position and individuals’ vulnerability to JIA.ConclusionIn brief, our findings suggest that the IL-2 −330 GG genotype together with IL-2 (−33-, +166) GT haplotype confers susceptibility to JIA, while IL-2 −330 GT genotype acts as a protective factor against JIA in an Iranian population. Nevertheless, further multicentre studies with larger sample size could be suggested so as to confirm the associations of the aforementioned polymorphisms of the IL-2 and IFN-γ genes with the proneness to JIA. Evaluation of IL-10 production could also be recommended in subsequent investigations.Ethical disclosuresConfidentiality of dataThe authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.Right to privacy and informed consentThe authors have obtained the informed consent of the patients and/or subjects mentioned in the article. The author for correspondence is in possession of this document.Protection of human subjects and animals in researchThe authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.FundingThis study was funded by Tehran University of Medical Sciences and Health Services (Grant Number: 92-03-30-24902).Conflict of interestThe authors have no conflict of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres688839" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec694625" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Sampling and genotyping" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Allele, genotype and haplotype frequencies" ] ] ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusion" ] 7 => array:3 [ "identificador" => "sec0050" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0085" "titulo" => "Confidentiality of data" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Right to privacy and informed consent" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "Protection of human subjects and animals in research" ] ] ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-05-24" "fechaAceptado" => "2015-10-07" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec694625" "palabras" => array:5 [ 0 => "Interleukin-2" 1 => "Interferon-gamma" 2 => "Single nucleotide polymorphism" 3 => "Juvenile idiopathic arthritis" 4 => "Children" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundCytokines, including interleukin-2 (IL-2) and interferon-gamma (IFN-γ), seem to play a role in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the associations of IL-2 and IFN-γ single nucleotide polymorphisms (SNPs) with susceptibility to JIA in an Iranian population. MethodsGenomic DNA of 54 Iranian patients with JIA and 139 healthy unrelated controls were typed for IL-2 (G/T at −330 and +166) as well as IFN-γ gene (A/T at +874), using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls. ResultsA significantly higher frequency of the IL-2 −330 GG genotype (p<0.01) was found in the JIA patients compared to the controls. However, the GT genotype at the same position was notably lower than in controls (p<0.01). Moreover, IL-2 (−330, +166) GT haplotype was more frequent in patients with JIA in comparison with controls. No significant differences was observed between the two groups of case and control for IL-2 (G/T at +166) and IFN-γ (A/T at +874) SNPs. ConclusionThe results of the current study suggest that certain SNPs of IL-2 gene have association with individuals’ susceptibility to JIA. However, further investigations are required to confirm the results of this study." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cytokine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Position \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Alleles/Genotypes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (N=139) N (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients (N=54) N (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Odds Ratio (95% CI) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p-value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="13" align="left" valign="middle">IL-2</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N=139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N=42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="middle">−330</td><td class="td" title="table-entry " align="left" valign="top">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">110 (39.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">38 (45.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.26 (0.75–2.12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.42 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">168 (60.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">46 (54.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.79 (0.47–1.34) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.42 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (5.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 (28.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.55 (2.24–19.50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">94 (67.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (33.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.24 (0.11–0.53) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 (26.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 (38.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.70 (0.77–3.73) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="6" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N=139 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N=42 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="middle">+166</td><td class="td" title="table-entry " align="left" valign="top">G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">219 (78.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">67 (79.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.06 (0.56–2.04) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">59 (21.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 (20.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.94 (0.49–1.79) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.97 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">82 (59) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">27 (64.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.25 (0.58–2.72) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.66 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">55 (39.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 (30.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.68 (0.31–1.51) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.41 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (1.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (4.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.42 (0.33–35.41) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.23 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="7" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N=138 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">N=54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="middle">IFN-γ</td><td class="td" title="table-entry " rowspan="5" align="left" valign="middle">+874</td><td class="td" title="table-entry " align="left" valign="top">A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">140 (50.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">66 (61.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.56 (0.97–2.53) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.07 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">136 (49.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">41 (38.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.64 (0.40–1.03) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.07 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">43 (31.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (38.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.38 (0.67–2.83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.43 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54 (39.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">23 (44.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.23 (0.62–2.47) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.64 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">41 (29.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9 (17.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.50 (0.20–1.18) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.12 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1120634.png" ] ] ] ] "descripcion" => array:1 [ "en" => "IL-2 and IFN-γ allele and genotype polymorphisms in patients with JIA and controls." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cytokine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Position \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Haplotype \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls (n=139) N (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients (n=54) N (%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Odds Ratio (95% CI) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p-value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="middle">IL-2</td><td class="td" title="table-entry " rowspan="4" align="left" valign="middle">−330, +166</td><td class="td" title="table-entry " align="left" valign="top">GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">107 (38.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35 (41.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.13 (0.67–1.91) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.73 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">112 (40.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 (38.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.90 (0.53–1.53) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.78 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56 (20.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14 (16.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.79 (0.39–1.56) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.56 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (0.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (3.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10.19 (0.93–257.61) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.04 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1120635.png" ] ] ] ] "descripcion" => array:1 [ "en" => "IL-2 haplotype polymorphism in patients with JIA and controls." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:21 [ 0 => array:3 [ "identificador" => "bib0110" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytokine single nucleotide polymorphisms in Iranian populations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.A. 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Original Article

M. Maddaha, S. Harsinib, A. Rezaeib, M. Sadrc, S. Zoghid, M.H. Moradinejada, V. Ziaeea,e, N. Rezaeib,c,d,f,

Corresponding author

rezaei_nima@tums.ac.ir

Corresponding author.

a Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

b Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

c Molecular Immunology Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

d Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

e Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran

f Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

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they do appear to have genetic risk factors in common&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">7</span></a> The common feature of all JIA subtypes is the presence of chronic inflammation within synovial joints&#44; in which cytokines play pivotal roles&#46; It has been previously suggested that certain single nucleotide polymorphisms &#40;SNPs&#41; within the promoter and coding sequences of various cytokines&#8217; genes&#44; which affect their level of production&#44; could be associated with the vulnerability to a group of autoimmune disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">4&#44;6&#44;10&#44;12&#44;21</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">In the current study&#44; we have selected two of the cytokines&#44; including interferon-gamma &#40;IFN-&#947;&#41; and interleukin-2 &#40;IL-2&#41;&#44; that have been reported previously to have a role in JIA aetiopathogenesis&#44;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">3&#44;19</span></a> to determine whether certain SNPs in these cytokines&#8217; genes are associated with susceptibility to JIA&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">It has been postulated that these genes may also confer susceptibility to JIA&#46; Therefore&#44; the aim of this study was to assess whether <span class="elsevierStyleItalic">IL-2</span> &#40;G&#47;T at &#8722;330 and &#43;166&#41; as well as <span class="elsevierStyleItalic">IFN-&#947;</span> &#40;A&#47;T at &#43;874&#41; gene polymorphisms are also associated with susceptibility to JIA in Iranian patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Study population</span><p id="par0020" class="elsevierStylePara elsevierViewall">A total of 54 consecutive JIA patients&#44; recruited from the Rheumatology Clinic of the Children&#39;s Medical Center Hospital&#44; the Paediatrics Center of Excellence in Iran&#44; were included in the case group and compared to 139 healthy unrelated individuals who were randomly selected from blood donors at Iranian blood transfusion organisations&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">1</span></a> Diagnosis of JIA was based on the ILAR classification criteria for JIA&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">17</span></a> Our patients&#8217; group comprised 24 individuals with oligoarticular JIA&#44; 19 with polyarticular JIA&#44; and 11 with systemic disease subtype&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Written informed consents were obtained from all entrants to this investigation&#44; and the study protocol was approved by the Ethical Committee of Tehran University of Medical Sciences&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Sampling and genotyping</span><p id="par0030" class="elsevierStylePara elsevierViewall">To obtain genomic DNA&#44; 5<span class="elsevierStyleHsp" style=""></span>mL of peripheral blood was collected from each patient and stored at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C in EDTA tubes until DNA extraction using the &#8220;salting out&#8221; technique&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">13</span></a> Polymerase chain reaction&#44; with sequence-specific primers method &#40;PCR-SSP assay kit&#59; Heidelberg University&#44; Germany&#41; was employed for cytokine gene typing according to the manufacturer&#39;s instructions&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">1</span></a> The three single nucleotide polymorphisms &#40;SNPs&#41; studied were <span class="elsevierStyleItalic">IL-2</span> &#40;G&#47;T at &#8722;330 and &#43;166&#41; and <span class="elsevierStyleItalic">IFN-&#947;</span> &#40;A&#47;T at &#43;874&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Statistical analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The allele&#44; genotype and haplotype frequencies were evaluated by direct gene counting and compared with the healthy controls using the chi square test&#46; The odds ratio &#40;OR&#41; and 95&#37; confidence interval &#40;CI&#41; were estimated for each allele&#44; genotype&#44; and haplotype in the patient and control groups&#46; Adherence to the Hardy&#8211;Weinberg equilibrium for each genotype was assessed for both case and control groups using the chi square test&#46; <span class="elsevierStyleItalic">P</span> values of less than 0&#46;05 were considered statistically significant&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Allele&#44; genotype and haplotype frequencies</span><p id="par0040" class="elsevierStylePara elsevierViewall">The allelic and genotype frequencies in patients with JIA and healthy controls are demonstrated in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">A positive genotypic association was detected for <span class="elsevierStyleItalic">IL-2</span> &#8722;330&#47;GG with JIA susceptibility &#40;28&#46;8&#37; vs&#46; 5&#46;8&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Meanwhile&#44; the GT genotype frequency at <span class="elsevierStyleItalic">IL-2</span> &#8722;330 in JIA patient was notably lower than in healthy individuals &#40;33&#46;3&#37; vs&#46; 67&#46;6&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; No significant difference was discovered between the two groups of case and control for <span class="elsevierStyleItalic">IL-2</span> &#40;G&#47;T at &#43;166&#41; and <span class="elsevierStyleItalic">IFN-&#947;</span> &#40;A&#47;T at &#43;874&#41; SNPs&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">At the haplotypic level&#44; <span class="elsevierStyleItalic">IL-2</span> &#40;&#8722;330&#44; &#43;166&#41; GT haplotype was found to be more frequent in patients with JIA in comparison with healthy controls &#40;3&#46;6&#37; vs&#46; 0&#46;3&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#41;&#46; We observed no significant differences between the two groups for GG&#44; TG and TT haplotypes at the same positions &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">In addition&#44; no significant difference was detected between the aforementioned gene polymorphisms and individuals&#8217; susceptibility to different JIA subtypes&#44; including systemic&#44; polyarticular&#44; and oligoarticular JIA&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Discussion</span><p id="par0060" class="elsevierStylePara elsevierViewall">This study aims at evaluating the association of <span class="elsevierStyleItalic">IL-2</span> &#40;&#8722;330 G&#47;T&#44; &#43;166 G&#47;T&#41; and <span class="elsevierStyleItalic">IFN-&#947;</span> &#40;&#43;874 A&#47;T&#41; single nucleotide polymorphisms in Iranian patients with JIA&#46; To the best of our knowledge&#44; ours is the first study to analyse the role of the above-said gene variants in susceptibility to JIA in an Iranian population&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Interleukin-2 &#40;IL-2&#41; is recognised as a typical T helper 1 &#40;Th1&#41; cytokine&#44; which exerts forceful modulatory effect on various immune cells&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> It has been proposed that dysfunction of the IL-2 could culminate in functional or pathological alterations in the immune system&#44; resulting in autoimmunity&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">8</span></a> It is widely accepted that <span class="elsevierStyleItalic">IL-2</span> expression is reduced in peripheral blood and both the synovial fluid and the synovium of patients with rheumatoid arthritis &#40;RA&#41; compared to healthy individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">11&#44;20</span></a> Furthermore&#44; IL-2 protein has previously been identified to be decreased in the sera of patients with systemic-onset JIA&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleItalic">IL-2</span> SNPs are the probable underlying causes of the variations found in IL-2 concentrations between patients and controls&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> Two single nucleotide polymorphisms have been recognised at &#8722;330 G&#47;T and &#43;166 G&#47;T positions from the transcription start site in <span class="elsevierStyleItalic">IL-2</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">9</span></a> The allele G at <span class="elsevierStyleItalic">IL-2</span> &#8722;330 position is known to be associated with higher levels of IL-2 production&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">1</span></a> In the present study&#44; we found overrepresentation of the GG genotype &#40;acknowledged as a polymorphism with an elevated level of IL-2 secretion<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">1</span></a>&#41; at <span class="elsevierStyleItalic">IL-2</span> &#8722;330 position in the patients group&#44; whilst the frequency of the GT genotype at the same position &#40;identified as a genotype with an intermediate level of cytokine gene expression<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">1</span></a>&#41; was found to be lower than the controls&#46; Moreover&#44; at the haplotype level&#44; we detected GT haplotype at <span class="elsevierStyleItalic">IL-2</span> &#40;&#8722;330&#44; &#43;166&#41; to be more frequent in patients with JIA compared to healthy individuals&#46; Our findings are in line with the results of the association study carried out by Pawlik et al&#46;&#44; which revealed the association of <span class="elsevierStyleItalic">IL-2</span> &#8722;330 GG genotype with RA severity&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">15</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Interferon-gamma &#40;IFN-&#947;&#41;&#44; a pleiotropic cytokine with antiviral properties&#44; is another Th1 cytokine&#44; which affects inflammation through promoting macrophages to secrete inflammatory and tissue-damaging mediators&#44; including proteases&#44; reactive oxygen species&#44; nitric oxide and tumour necrosis factor alpha &#40;TNF-&#945;&#41;&#44; as well as enhancing major histocompatibility complex &#40;MHC&#41; class II expression&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">5</span></a> This cytokine is found in the synovial tissue and in the fluid of RA patients&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">2</span></a> In addition&#44; changes in the levels of IFN-&#947; protein have been previously reported in the sera of patients with systemic-onset JIA&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">11</span></a> As the <span class="elsevierStyleItalic">IFN-&#947;</span> gene polymorphisms may be the plausible candidates for individuals&#8217; proneness to JIA&#44; the functional SNP at <span class="elsevierStyleItalic">IFN-&#947;</span> &#43;874 position&#44; which maps to a putative nuclear factor-kB &#40;NF-kB&#41; binding site&#44; has been analysed in the current study&#46; The presence of T allele at the afore-mentioned position enhances the NF-kB binding efficiency resulting in elevated IFN-&#947; production&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">18</span></a> In the present study&#44; we did not detect any association between SNPs at <span class="elsevierStyleItalic">IFN-&#947;</span> &#43;874 position and individuals&#8217; vulnerability to JIA&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusion</span><p id="par0075" class="elsevierStylePara elsevierViewall">In brief&#44; our findings suggest that the <span class="elsevierStyleItalic">IL-2</span> &#8722;330 GG genotype together with <span class="elsevierStyleItalic">IL-2</span> &#40;&#8722;33-&#44; &#43;166&#41; GT haplotype confers susceptibility to JIA&#44; while <span class="elsevierStyleItalic">IL-2</span> &#8722;330 GT genotype acts as a protective factor against JIA in an Iranian population&#46; Nevertheless&#44; further multicentre studies with larger sample size could be suggested so as to confirm the associations of the aforementioned polymorphisms of the <span class="elsevierStyleItalic">IL-2</span> and <span class="elsevierStyleItalic">IFN-&#947;</span> genes with the proneness to JIA&#46; Evaluation of IL-10 production could also be recommended in subsequent investigations&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ethical disclosures</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Confidentiality of data</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Right to privacy and informed consent</span><p id="par0085" class="elsevierStylePara elsevierViewall">The authors have obtained the informed consent of the patients and&#47;or subjects mentioned in the article&#46; The author for correspondence is in possession of this document&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protection of human subjects and animals in research</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Funding</span><p id="par0095" class="elsevierStylePara elsevierViewall">This study was funded by <span class="elsevierStyleGrantSponsor" id="gs1">Tehran University of Medical Sciences and Health Services</span> &#40;Grant Number&#58; <span class="elsevierStyleGrantNumber" refid="gs1">92-03-30-24902</span>&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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              "titulo" => "Allele&#44; genotype and haplotype frequencies"
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    "fechaRecibido" => "2015-05-24"
    "fechaAceptado" => "2015-10-07"
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            0 => "Interleukin-2"
            1 => "Interferon-gamma"
            2 => "Single nucleotide polymorphism"
            3 => "Juvenile idiopathic arthritis"
            4 => "Children"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cytokines&#44; including interleukin-2 &#40;IL-2&#41; and interferon-gamma &#40;IFN-&#947;&#41;&#44; seem to play a role in the pathogenesis of juvenile idiopathic arthritis &#40;JIA&#41;&#46; The aim of this study was to investigate the associations of <span class="elsevierStyleItalic">IL-2</span> and <span class="elsevierStyleItalic">IFN-&#947;</span> single nucleotide polymorphisms &#40;SNPs&#41; with susceptibility to JIA in an Iranian population&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Genomic DNA of 54 Iranian patients with JIA and 139 healthy unrelated controls were typed for <span class="elsevierStyleItalic">IL-2</span> &#40;G&#47;T at &#8722;330 and &#43;166&#41; as well as <span class="elsevierStyleItalic">IFN-&#947;</span> gene &#40;A&#47;T at &#43;874&#41;&#44; using polymerase chain reaction with sequence-specific primers method&#44; and compared between patients and controls&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A significantly higher frequency of the <span class="elsevierStyleItalic">IL-2</span> &#8722;330 GG genotype &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; was found in the JIA patients compared to the controls&#46; However&#44; the GT genotype at the same position was notably lower than in controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Moreover&#44; <span class="elsevierStyleItalic">IL-2</span> &#40;&#8722;330&#44; &#43;166&#41; GT haplotype was more frequent in patients with JIA in comparison with controls&#46; No significant differences was observed between the two groups of case and control for <span class="elsevierStyleItalic">IL-2</span> &#40;G&#47;T at &#43;166&#41; and <span class="elsevierStyleItalic">IFN-&#947;</span> &#40;A&#47;T at &#43;874&#41; SNPs&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The results of the current study suggest that certain SNPs of <span class="elsevierStyleItalic">IL-2</span> gene have association with individuals&#8217; susceptibility to JIA&#46; However&#44; further investigations are required to confirm the results of this study&#46;</p></span>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cytokine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Position&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Alleles&#47;Genotypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls &#40;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139&#41;<br>N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients &#40;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;<br>N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Odds Ratio &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="13" align="left" valign="middle">IL-2</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">139</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">42</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">&#8722;330</td><td class="td" title="table-entry  " align="left" valign="top">G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">110 &#40;39&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">38 &#40;45&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;26 &#40;0&#46;75&#8211;2&#46;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">168 &#40;60&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 &#40;54&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;79 &#40;0&#46;47&#8211;1&#46;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">GG</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">8 &#40;5&#46;8&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">12 &#40;28&#46;6&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">6&#46;55 &#40;2&#46;24&#8211;19&#46;50&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">&#60;0&#46;01</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">GT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">94 &#40;67&#46;6&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">14 &#40;33&#46;3&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">0&#46;24 &#40;0&#46;11&#8211;0&#46;53&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">&#60;0&#46;01</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37 &#40;26&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16 &#40;38&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;70 &#40;0&#46;77&#8211;3&#46;73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="6" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">139</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">42</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">&#43;166</td><td class="td" title="table-entry  " align="left" valign="top">G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">219 &#40;78&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">67 &#40;79&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;06 &#40;0&#46;56&#8211;2&#46;04&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#40;21&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;20&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;94 &#40;0&#46;49&#8211;1&#46;79&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82 &#40;59&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 &#40;64&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;25 &#40;0&#46;58&#8211;2&#46;72&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55 &#40;39&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;30&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;68 &#40;0&#46;31&#8211;1&#46;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;1&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;42 &#40;0&#46;33&#8211;35&#46;41&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">138</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleBold">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleBold">54</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">IFN-&#947;</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">&#43;874</td><td class="td" title="table-entry  " align="left" valign="top">A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">140 &#40;50&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">66 &#40;61&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;56 &#40;0&#46;97&#8211;2&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">136 &#40;49&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">41 &#40;38&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;64 &#40;0&#46;40&#8211;1&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;31&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;38&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;38 &#40;0&#46;67&#8211;2&#46;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">AT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#40;39&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23 &#40;44&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;23 &#40;0&#46;62&#8211;2&#46;47&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">41 &#40;29&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;17&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;50 &#40;0&#46;20&#8211;1&#46;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">IL-2 and IFN-&#947; allele and genotype polymorphisms in patients with JIA and controls&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cytokine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Position&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Haplotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Controls &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139&#41;<br>N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#41;<br>N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Odds Ratio &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="middle">IL-2</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="middle">&#8722;330&#44; &#43;166</td><td class="td" title="table-entry  " align="left" valign="top">GG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">107 &#40;38&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;13 &#40;0&#46;67&#8211;1&#46;91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">112 &#40;40&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32 &#40;38&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;90 &#40;0&#46;53&#8211;1&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">56 &#40;20&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14 &#40;16&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;79 &#40;0&#46;39&#8211;1&#46;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">GT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">1 &#40;0&#46;3&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">3 &#40;3&#46;6&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">10&#46;19 &#40;0&#46;93&#8211;257&#46;61&#41;</span>&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2015.10.005

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	8	0	8
2024 October	19	6	25
2024 September	44	19	63
2024 August	48	25	73
2024 July	37	3	40
2024 June	18	8	26
2024 May	30	4	34
2024 April	22	7	29
2024 March	34	7	41
2024 February	35	3	38
2024 January	46	10	56
2023 December	27	7	34
2023 November	36	4	40
2023 October	43	8	51
2023 September	43	7	50
2023 August	52	5	57
2023 July	52	7	59
2023 June	51	3	54
2023 May	52	1	53
2023 April	13	0	13
2023 March	21	2	23
2023 February	33	4	37
2023 January	28	2	30
2022 December	22	11	33
2022 November	29	9	38
2022 October	21	7	28
2022 September	28	8	36
2022 August	25	6	31
2022 July	25	7	32
2022 June	38	8	46
2022 May	39	10	49
2022 April	71	13	84
2022 March	92	6	98
2022 February	106	10	116
2022 January	83	3	86
2021 December	59	14	73
2021 November	52	10	62
2021 October	17	18	35
2021 September	18	5	23
2021 August	15	8	23
2021 July	10	9	19
2021 June	18	7	25
2021 May	15	12	27
2021 April	33	6	39
2021 March	20	11	31
2021 February	10	15	25
2021 January	12	2	14
2020 December	1	0	1
2020 October	1	0	1
2020 July	0	1	1
2018 February	2	0	2
2018 January	5	2	7
2017 December	2	0	2
2017 November	7	0	7
2017 October	4	3	7
2017 September	8	1	9
2017 August	1	0	1
2017 July	4	1	5
2017 June	11	2	13
2017 May	3	1	4
2017 April	0	1	1
2016 July	4	3	7

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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