BACKGROUND Low-dose oral immunotherapy (OIT) is a safe treatment for hen's egg allergy; however, comparison of its therapeutic effects with those of high-dose OIT has not been reported. OBJECTIVE To compare the efficacy of low- and high-dose boiled egg-white (EW) OIT for hen's egg allergy. METHODS Patients with hen's egg allergy were randomly assigned to two groups: OIT using hard-boiled EW with a maximum maintenance dose of 2 and 20 g in the low-dose (L-D) and high-dose (H-D) groups, respectively. The intake dose was ingested twice a week, increased by approximately 20% per week until reaching the target maintenance dose (2 or 20 g hard-boiled EW), and maintained thereafter according to the schedule. The threshold was confirmed via oral food challenge (OFC) after 6 months, and the difference in the proportion of subjects passing the exit OFC between groups was evaluated. RESULTS Fifty-two patients (L-D, n = 23; H-D, n = 29) were enrolled. Thirty-three patients (L-D, n = 17; H-D, n = 16) completed the 6-month OIT and underwent an exit OFC. In total, three (L-D, 3/17; H-D, 3/16) patients in each group tested negative for an exit OFC with a 20-g reactive dose (p = 1.000). EW-specific IgE levels in both groups decreased significantly after OIT (L-D, p < 0.001; H-D, p = 0.002). CONCLUSIONS A threshold-elevating effect was observed in the L-D group, not inferior to that in the H-D group. Low-dose OIT may be appropriate to treat hen's egg allergy for the first 6 months.

Introduction:Oral immunotherapy (OIT) has been reported to be effective but associated with a risk of severe symptoms. Thus, an OIT method with decreased risk is required.Objectives:We aimed to evaluate the efficacy and safety of low- and high-dose OIT regimens in children with severe milk allergy.Methods:Overall, 33 participants (median age, 9 years; median final dose of the milk oral food challenge [OFC], 2 mL) were included. The participants were randomly assigned to groups that received either a low (20 mL;n= 19) or high (100 mL;n= 14) maintenance target dose of OIT. The dose was gradually increased to the target dose in the rush escalation phase and was then maintained daily at home. The primary endpoint was the final OFC dose at 6 months of OIT. Adverse events during OIT were evaluated.Results:The final OFC dose after OIT was significantly higher than that before OIT in both groups (low-dose,p= 0.000; high-dose,p= 0.006), but there was no significant difference in the final OFC dose between the 2 groups (p= 0.767). In the maintenance phase, the high-dose group had significantly more severe symptoms than did the low-dose group (0.5%, 11/2,355 total intake events vs. 0.1%, 4/3,230 total intake events;p= 0.018).Conclusions:An equally increased dose effect was observed for maintenance OIT doses of 20 and 100 mL in children with severe milk allergy. The risk of severe symptoms in the maintenance phase was lower in the low-dose group. A low-dose OIT regimen is recommended for severe milk allergy.

Abstract Introduction Restrictive cardiomyopathy (RCM) is a rare myocardial disease with an impaired diastolic function and poor prognosis. The mean survival duration after a diagnosis of RCM is reported to be around 2 years in children and most need heart transplantations. Purpose This study aimed to determine the 12-lead electrocardiogram (ECG) diagnostic criteria of RCM based on the initial diagnostic electrocardiogram. Methods ECGs in pediatric cardiomyopathy patients were collected from 15 institutes in Japan between 1979 and 2013. We compared the ECG findings, especially of the P wave, in RCM patients between the cardiomyopathy group and healthy children group separately for each gender and the age. The ECGs in the healthy group were obtained from school heart screening in Japan of first-graders, and seventh-graders. Statistical significance was determined as p<0.001. Results Among 376 registered cardiomyopathy patients, 63 had hypertrophic cardiomyopathy (HCM) (36%), 91 (24%) dilated cardiomyopathy (DCM), 106 (28%) a left ventricular myocardial noncompaction (LVNCs), 25 (7%) restrictive cardiomyopathy (RCM), 14 (4%) arrhythmogenic right ventricular cardiomyopathy (ARVC), and 5 (1%) other cardiomyopathies. Of the 25 RCM patients (9.9±3.4 years old, F:M=11:14), 36% were discovered during school heart screening. The first onset was an abnormal ECG in 9, symptoms of heart failure in 6, respiratory tract infections in 3, syncope in 1, and 6 with other. Of those patients, 2 (8%) had a family history of RCM, 24 (92%) no family history. A genetic diagnosis was performed in 5 of the 25 cases, and 3 had genetic abnormalities related to RCM. The mean follow-up period was 65±95 months (mean±standard deviation). During follow up, 19 patients (76%) survived, 6 (24%) died, 7 (28%) had heart transplantations, and 3 (12%) were waiting for heart transplantations with a left ventricular assist device. The P wave was bimodal in lead I or biphasic in lead V1 in 15 patients (93%), and 13 (81%) patients had both variations. We evaluated the duration and amplitude of the first and second component of the P wave as P1 and P2. The number of control and RCM patients (control/RCM), duration of P1+P2, and sum total absolute value of the amplitude of P1+P2 in lead V1 were 8350/5, 90±9/116±10ms, and 72±28/528±278μV in first grade boys, 8423/3, 91±10/120±22ms, and 66±28/326±229μV in first grade girls, 8943/1, 97±1/100ms, and 71±31/328μV in seventh grade boys, and 9183/5, 98±11/112±10ms, and 55±27/315±56μV in seventh grade girls. Although the number of patients in the RCM group was small, sum total absolute value of the amplitude of P1+P2 in lead V1 showed a significant difference in any group. Conclusion The ECG in children with RCM exhibits P wave abnormalities in almost all patients. In particular, not the P wave interval but P wave shape in I and V1 and the sum total absolute value of the amplitude of P1+P2 in lead V1 were observed differences.

Steroid inhalation is the standard bronchial asthma therapy and it includes powdered metered doses, dry powder, and nebulizer suspension. However, particle sizes vary widely. The research goal was to demonstrate that different budesonide administration forms and devices have various deposition rates in the airway obstruction region. Here, we compared relative inhalation therapy efficacies and identified therapies that delivered the highest drug doses to the airway obstruction region. Weibel's anatomy data were used to identify the airway obstruction region in asthma. Based on European Standardization Committee data, we investigated the diameters of the drug particles being deposited there and evaluated the average particle size and distribution of the budesonide dosage forms and application devices. Drug dose depositions were measured by HPLC at each stage of a Cascade Impactor. Weibel's anatomy data indicated that the 1st–4th bronchial generations comprised the airway obstruction region and corresponded to the tracheobronchial area. According to the European Standardization, particles 2–6 µm in diameter were readily deposited there. The proportions of particles in this size range were 33.0%, 32.0%, 59.0%, and 78.0% for Turbuhaler, Symbicort, mesh-type NE-U22 suspension, and jet-type NE-C28 suspension, respectively. We localized the airway obstruction regions of bronchial asthma and identified the optimal inhalation therapy particle size. An electric nebulizer was more efficacious for budesonide administration than dry powder delivery. The NE-C28 treatment deposited 2.36x more budesonide in the airway obstruction region than dry powder delivery systems.

BACKGROUND Eosinophilic pneumonia is recognized both as an eosinophil-associated disease and as bronchial asthma. In eosinophilic pneumonia, the site of eosinophilic infiltration is mainly the alveolus and the peripheral airway; the disability of pulmonary function is restrictive, as opposed to from bronchial asthma, which has a relatively central side bronchus region and obstructive function. Differences in inflammatory region and the activation degree of T-cell and eosinophil parameters were predicted. CASE REPORT To determine the extent of inflammation and the region showing the inflammation in eosinophilic pneumonia, parameters like HLADRCD4/CD4 (%), CD25CD4/CD4 (%), ECP, soluble IL2R, and IL5 were examined in BALF and in peripheral blood during the active phase and remission phase. The percentage of HLADRCD4/CD4, IL-5, and the percentage of CD25CD4/CD4 were extremely high during the acute phase in BALF as compared to that in peripheral blood during the active and the remission phase. To avoid the adverse effects of systemic administration of steroids, we tried 5 different kinds of steroid through inhalation. We used%FVC by spirometry as a parameter to determine the recurrence of the disease. However, the inhaled steroids could not control the remission for long. This is the first report in which frequent recurrence of the disease was seen despite treatments and in which%FVC was used to determine the disease condition. CONCLUSIONS The principle site of inflammation in eosinophilic pneumonia is the peripheral bronchus and the alveolar area. Percent FVC can be a useful parameter for assessment of recurrence of the disease. In the present case, the disease could not be kept under control despite treatment with 5 different steroids through the inhalation route.

Introduction: The usefulness of low-dose oral immunotherapy (OIT) for the treatment of egg allergy has been unclear. Objective: To evaluate the efficacy and safety of OIT with low allergen cookies (LACs) containing a low dose of hen’s egg. Method: Thirty-three patients with severe hen’s egg allergy were randomly administered either OIT with LACs (n = 21) or placebo (n = 12). Two patients in the LACs group withdrew before completing OIT. The primary endpoint was the number of good responders (G-R), patients with negative results in the oral food challenge (OFC) with a final dose of 2 g hard-boiled egg whites after 4 months of OIT, in each group. Total OFC Aichi score for anaphylaxis/cumulative protein dose (TS/Pro) as the marker of severity of food allergy was also compared. Adverse events during OIT were evaluated using patients’ diaries. Results: The proportion of G-R in the LACs group was higher than in the placebo group (7/19 [37%] vs. 1/12 [8%], χ2 test; p = 0.077). The TS/Pro after OIT in the LACs group was lower than in the placebo group (median score, 44.2 vs. 104.1, p = 0.059; Mann-Whitney U test). The threshold and TS/Pro before and after OIT significantly improved in the LACs group (p = 0.015, p = 0.027, respectively; Wilcoxon signed-rank test). There were 99 recorded incidences of symptoms of 1,938 intake events in the LACs group during OIT. Of these, 90 were mild; no severe symptoms occurred. Conclusions: OIT with LACs potentially increases the OFC threshold and decreases allergy severity and is a relatively safe treatment modality.

Serum levels of total immunoglobulin E (IgE) and allergen-specific IgE are related to asthma severity and risk factors for persistent asthma in childhood wheezing. Inhaled corticosteroids (ICS) have been the most effective therapy in children with asthma, as well as in adults. The serum levels of total and mite specific IgE in children with asthma and the effects on IgE levels of beclomethasone dipropionate (BDP) treatment on IgE levels in asthmatic children were investigated. First, a cross-sectional study of 255 children with asthma was carried out to measure IgE levels. Children under three years of age with asthma who were negative for Df-specific IgE were then treated with BDP or disodium cromoglycate (DSCG) as controls for one year. Serum IgE levels, numbers of eosinophils in peripheral blood and clinical variables were determined before and after treatment. After one-year DSCG treatment, the total IgE levels increased significantly, whereas the levels remained the same during BDP treatment. Five of 22 (23%) patients in the DSCG-treated group became positive for Df-specific IgE; however, only one of 13 (8%) in the BDP-treated group became positive. Taken together, ICS therapy may modulate the levels of total IgE and allergen-specific IgE.

Background: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma. Methods: Thirty-eight Japanese children (aged 7-16 years) who completed the 24-week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886). Results: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9-151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p < 0.001 for QOL, 1.33 vs 0.16, p < 0.001 for hospitalization, 0.68 vs 0.15, p = 0.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state. Conclusions: Long-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified. Copyright (C) 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

Among inhaled asthma therapies, the present study aimed to identify factors for selecting the type of inhalation therapy for asthma. Three methods are used to deliver inhaled cromoglycate, and the airway deposition rate was evaluated using a cascade impactor with 3 dosage forms: dry powder (DP), pressurized metered dose inhaler (pMDI), and solution (jet- and mesh-types). The percentage of particles with diameters of 2–6 μm was 17.0% for the capsule, 51.8% for pMDI, 49.0% for jet-type NE-C28, and 40.4% for mesh-type NE-U22. The amounts of drug deposited in the bronchi were based on the particle distribution of the various dosage forms: 3.4 mg for the capsule, 1.0 mg for pMDI, 9.8 mg for one solution (jet-type NE-C28), and 8.1 mg for the other solution (mesh-type NE-U22). Jet-type or mesh-type electric nebulizers delivered 2-3 times more of the drug than capsules, and, compared with pMDI, 8-9 times more of the drug was deposited in the bronchi/bronchioles. Electric nebulizers are considered the best method. This study suggests that the size of particles deposited at sites of obstruction is larger than previously reported, and no obstruction of small airways occurs (<2 mm).

Food allergy (FA) is a public problem throughout the world and the prevalence rates of IgE-mediated FA in children are increasing in westernized countries.1 There appear to be both environmental and genetic predisposing factors for FA development; however, the genetic components of FA in children remain largely unexplored.1 Genome-wide association studies (GWAS) have convincingly identified candidate genes for a wide variety of allergic diseases, and shared susceptibility loci have been found across the diseases.

Background: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. Methods: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900). Results: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. Conclusions: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU. Copyright (C) 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

OBJECTIVE:We performed a constructive study on the effectiveness of oral immunotherapy for wheat allergy using two different intake frequency, and evaluated the impact of intake frequency.SUBJECTS:Of all the subjects who had a positive result in an oral food challenge test for udon (wheat noodles), informed consent was obtained from 49 subjects. Forty-one of the subjects successfully completed testing; data was tabulated for only the 16 in each group who complied with their assigned intake frequency.METHOD:Oral immunotherapy was administered after randomly dividing the subjects into the following two groups according to intake frequency: the frequent group, whose intake was six times/week or more; and the intermittent group, whose intake was two times/week. The ability of these patients to ingest the noodles at the target dose was evaluated after 6 months.RESULTS:After six months, the proportion of subjects who had a negative result on testing with the target dose (20g dried noodle weight for subjects ≤3 years of age, and 50g dried noodle weight for those ≥4 years of age) or who were capable of the target intake within six months was 75%, and there was no difference among the both groups.CONCLUSION:The findings suggest that even when intake frequency is reduced to twice/week, no clear difference is seen with the target dose after six months of immunotherapy.

BACKGROUND:In abroad, Methacholine Chloride (Provocholine®) is used to meet the indications of the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma. We examined efficacy, safety and pharmacokinetics of Methacholine Chloride (name of study drug: SK-1211) in order to get approved for the airway hyperresponsiveness test in Japan.METHODS:Fifteen adult healthy volunteers, fifteen adult patients with asthma and ten pediatric patients with asthma were enrolled in this study. The airway hyperresponsiveness test with SK-1211 was conducted in accordance with Japanese Society of Allergology Standard Method.RESULTS:When the threshold value of PC20 was 8 mg/mL, the sensitivity of adult patients with asthma was 66.7% (10/15 subjects) and the specificity of adult healthy volunteers was 86.7% (13/15 subjects). The sensitivity of pediatric patients with asthma was 70.0% (7/10 subjects). Not all subjects experienced some adverse reactions during inhalation of SK-1211, all of which were mild in severity and resolved soon with inhalation of a bronchodilator. There were no serious adverse reactions reported.CONCLUSION:The airway hyperresponsiveness test with SK-1211 was no specific concern with safety and useful in the diagnosis of bronchial airway hyperresponsiveness.

Background: Omalizumab has demonstrated clinical benefits in children with moderate to severe allergic asthma. However, no studies have been performed in Japanese asthmatic children. The aim of this study was to evaluate the efficacy including free IgE suppression and safety of omalizumab in Japanese children with severe allergic asthma. The primary objective was to examine whether omalizumab decreases serum free IgE levels to less than 25 ng/ml (target level of suppression).Methods: Thirty-eight Japanese children (6-15 years) with uncontrolled severe allergic asthma despite inhaled corticosteroids (>200 mu g/day fluticasone propionate or equivalent) and two or more controller therapies received add-on treatment with omalizumab in a 24-week, multicenter, uncontrolled, open-label study.Results: The geometric mean serum free IgE level at 24 weeks was 15.6 ng/mL. Compared with baseline, total asthma symptom scores, daily activity scores and nocturnal sleep scores at 24 weeks were significantly improved. The rates of asthma exacerbation and hospitalization due to asthma were reduced by 69.2% and 78.2%, respectively (p < 0.001), versus baseline. Quality-of-life scores were also significantly improved (p < 0.001). In addition, 11 (28.9%) patients reduced the dose of any asthma controller medications. Thirty-six (94.7%) patients experienced at least one adverse event during the treatment period. All adverse events were mild or moderate in severity and no new safety concerns were detected. No patients discontinued the study.Conclusions: In Japanese children with severe allergic asthma, omalizumab decreased free IgE levels to less than 25 ng/mL. Omalizumab improved asthma control and was well-tolerated, as well. Copyright (C) 2015, Japanese Society of Allergology. Production and hosting by Elsevier B.V.

Psoriasis vulgaris (PsV) is an inflammatory skin disease histologically characterized by epidermal hyperplasia, inflammatory cell infiltration and vascular changes. A dysregulated cutaneous immune response occurs in genetically susceptible individuals, and the features of inflammation are characterized by tumor necrosis factor (TNF)-α dependence and exaggerated helper T cell 17 (Th17) activation. Interleukin (IL)-17 produced by Th17 cells plays a pivotal role in the pathogenesis of PsV, and administration of an antibody specific to IL-17 or IL-17 receptor (IL-17R) to psoriasis patients is extremely efficacious [ 1 Leonardi C. Matheson R. Zachariae C. Cameron G. Li L. Edson-Heredia E. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012; 336: 1190-1199 Crossref Scopus (781) Google Scholar , 2 Papp K.A. Leonardi C. Menter A. Ortonne J.-P. Krueger J.G. Kricorian G. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012; 366: 1181-1189 Crossref PubMed Scopus (780) Google Scholar ]. In 2010, European genome-wide association studies (GWASs) of PsV identified a new susceptibility locus containing the TNF receptor-associated factor 3-interacting protein 2 (TRAF3IP2) gene [ 3 Ellinghaus E. Ellinghaus D. Stuart P.E. Nair R.P. Debrus S. Raelson J.V. et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet. 2010; 42: 991-995 Crossref PubMed Scopus (272) Google Scholar , 4 Hüffmeier U. Uebe S. Ekici A.B. Bowes J. Giardina E. Korendowych E. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriasis arthritis and psoriasis. Nat Genet. 2010; 42: 996-999 Crossref PubMed Scopus (291) Google Scholar ]. The TRAF3IP2 gene encodes a protein involved in IL-17 signaling, which interacts with members of the nuclear factor-kappa-B (NF-κB) transcription factor family. Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that is basically considered to be a Th-2 type disease. However, a recent study suggests a possible role of Th17 cells in AD. The study has shown that the number of Th17 cells is increased in the peripheral blood and acute lesional skin of AD [ [5] Koga C. Kabashima K. Shiraishi N. Kobayashi M. Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008; 128: 2625-2630 Crossref PubMed Scopus (504) Google Scholar ]. Furthermore, mice carrying a spontaneous recessive point mutation in the TRAF3IP2 gene result in an AD-like skin with hyper-IgE-emia [ [6] Matsushima Y. Kikkawa Y. Takada T. Matsuoka K. Seki Y. Yoshida H. et al. An atopic dermatitis-like skin disease with hyper-IgE-emia develops in mice carrying a spontaneous recessive point mutation in the Traf3ip2 (Act1/CIKS) gene. J Immunol. 2010; 185: 2340-2349 Crossref PubMed Scopus (27) Google Scholar ]. These findings suggest important roles of the TRAF3IP2 gene in the pathogenesis of AD. Since there has been few genetic studies of the polymorphisms of TRAF3IP2, we conducted association studies to assess whether TRAF3IP2 gene variants contribute to the susceptibility to PsV or AD in the Japanese population.

Psoriasis is a chronic inflammatory skin disease caused by interplay between genetic and environmental factors, and psoriasis vulgaris (PsV) is the most common form of the disease [[1]Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2135) Google Scholar]. Recent genome-wide association studies (GWASs) and meta-analysis of GWAS of psoriasis in European individuals have identified a total of 36 susceptibility loci at a genome-wide level of significance (P < 5 × 10−8) [[2]Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. et al.Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (680) Google Scholar]. Conditional analysis of the 36 loci was also conducted and further identified five additional SNPs, rs2111485, rs2910686, rs4379175, rs13437088 and rs12720356 with genome-wide significance. We conducted a validation study of these 41 SNPs among the 36 loci in Japanese patients with PsV. Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and recent linkage and association studies have identified overlapping susceptibility loci of psoriasis and AD [3Elder J.T. Bruce A.T. Gudjonsson J.E. Johnston A. Stuart P.E. Tejasvi T. et al.Molecular dissection of psoriasis: integrating genetics and biology.J Invest Dermatol. 2010; 130: 1213-1226Crossref PubMed Scopus (232) Google Scholar, 4Weidinger S. Willis-Owen S.A. Kamatani Y. Baurecht H. Morar N. Liang L. et al.A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.Hum Mol Genet. 2013; 22: 4841-4856Crossref PubMed Scopus (143) Google Scholar]. Since identification of shared genetic components helps to highlight the key molecular pathways involved in chronic inflammatory skin diseases, we also explored the association of these 41 SNPs in Japanese patients with AD.We recruited a total of 259 patients with PsV diagnosed by clinical and histopathological findings (median age 53, 11–85 years, male:female ratio = 2.4:1.0) and a total of 999 patients with AD diagnosed according to the criteria of Hanifin and Rajka (median age 29, 3–77 years, male:female ratio = 1.3:1.0). As controls, 938 individuals who had never been diagnosed with AD or PsV were recruited from Fukui University and Miyatake Clinic (median age 50, 20–75 years, male:female ratio = 2.0:1.0). All individuals were unrelated Japanese and gave written informed consent to participate in the study. The study was approved by the ethical committees of the hospitals involved, the University of Tokyo, the Jikei University School of Medicine, Fukui University, Miyatake Clinic and the Institute of Physical and Chemical Research (RIKEN). Genomic DNA was prepared in accordance with standard protocols. We selected a total of 41 SNPs achieving genome-wide significance in a previous meta-analysis of GWASs [[2]Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. et al.Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (680) Google Scholar]. SNPs were genotyped by using the multiplex PCR-based Invader assay (Third Wave Japan). We calculated allele frequencies and tested agreement with Hardy–Weinberg equilibrium using a χ2 goodness of fit test as described [[5]Hirota T. Takahashi A. Kubo M. Tsunoda T. Tomita K. Sakashita M. et al.Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population.Nat Genet. 2012; 44: 1222-1226Crossref PubMed Scopus (246) Google Scholar], and no SNP was excluded from the analysis. Among 41 SNPs, four (rs9988642, rs12188300, rs34536443 and rs12720356) were found to be monomorphic in this study. We compared differences in the allele frequencies of the 37 polymorphisms between case and control subjects by using a contingency χ2 test or Fisher's exact test, and calculated odds ratios (ORs) with 95 percent confidence intervals (95% CI). We then applied Bonferroni corrections, the multiplication of P values by the number SNPs assessed (n = 37). Statistical significance was set at P < 0.05.All genotype frequencies and statistical results are shown in Table 1 and Supplementary Tables S1 and S2. We found significant associations with PsV in four SNPs, TNIP1 (rs2233278, P = 3.5 × 10−8), IL12B (rs4379175, P = 1.2 × 10−6), the MHC class I region (rs4406273, P = 5.9 × 10−7) and TRAF3IP2 (rs33980500, P = 9.4 × 10−6), after Bonferroni correction for 37 tests with P < 1.4 × 10−3 (0.05/37) (Table 1). The direction of associations of susceptibility to PsV was similar to that in the recent study [[2]Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. et al.Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (680) Google Scholar], and confirmed previous Japanese studies that have shown significant associations with IL12B [[6]Tsunemi Y. Saeki H. Nakamura K. Sekiya T. Hirai K. Fujita H. et al.Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.J Dermatol Sci. 2002; 30: 161-166Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar], TRAF3IP2 [[7]Hayashi M. Hirota T. Saeki H. Nakagawa H. Ishiuji Y. Matsuzaki H. et al.Genetic polymorphism in the TRAF3IP2 gene is associated with psoriasis vulgaris in a Japanese population.J Dermatol Sci. 2014; 73: 264-265Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] and the MHC class I region [[8]Oka A. Tamiya G. Tomizawa M. Ota M. Katsuyama Y. Makino S. et al.Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene.Hum Mol Genet. 1999; 8: 2165-2170Crossref PubMed Scopus (149) Google Scholar]. The strongest association was observed in Japanese patients with PsV for the first time at TNIP for SNP rs2233278, and TNIP encodes ABIN-1, an A20-binding protein that links A20 to NEMO/IKKγ and results in inhibition of NF-κB by facilitation of A20-mediated deubiquitination of NEMO/IKKγ [[9]Mauro C. Pacifico F. Lavorgna A. Mellone S. Iannetti A. Acquaviva R. et al.ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-κB.J Biol Chem. 2006; 281: 18482-18488Crossref PubMed Scopus (202) Google Scholar].Table 1Summary of allele frequencies of 37 previously reported loci for psoriasis.dbSNPGeneControln = 938PsVn = 259ADn = 999P valuePsVP valueADMAFMAFMAFOR (95% CI)OR (95% CI)rs11121129SLC45A1, TNFRSF90.2220.2300.2277.19E−011.04 (0.83–1.32)7.16E−011.03 (0.88–1.20)rs7552167IL28RA0.1920.1410.1968.12E−030.69 (0.53–0.91)7.86E−011.02 (0.87–1.20)rs7536201RUNX30.3880.3440.3586.55E−020.83 (0.67–1.01)5.40E−020.88 (0.77–1.00)rs6677595LCE3B, LCE3D0.4120.3630.4174.52E−020.81 (0.67–1.00)7.33E−011.02 (0.90–1.16)rs62149416FLJ16341, REL0.0390.0430.0386.70E−011.11 (0.68–1.81)8.73E−010.97 (0.70–1.36)rs10865331B3GNT20.3150.3470.3111.67E−011.16 (0.94–1.42)7.97E−010.98 (0.86–1.13)rs2111485IFIH10.1730.1810.1746.72E−011.06 (0.82–1.36)9.03E−011.01 (0.85–1.19)rs17716942KCNH7, IFIH10.0000.0000.001––3.30E−01–rs27432ERAP10.4060.3730.3821.73E−010.87 (0.71–1.06)1.30E−010.90 (0.79–1.03)rs2910686ERAP20.4840.5160.5102.10E−011.13 (0.93–1.38)1.19E−011.11 (0.97–1.26)rs1295685IL13, IL40.3020.2740.3462.18E−010.87 (0.70–1.08)3.54E−031.22 (1.07–1.40)rs2233278TNIP10.0890.1740.0863.50E−082.15 (1.63–2.84)7.34E−010.96 (0.77–1.20)rs4379175IL12B0.4300.3110.4501.25E−060.60 (0.49–0.74)2.02E−011.09 (0.96–1.23)rs9504361EXOC2, IRF40.2170.2340.2134.00E−011.10 (0.88–1.39)7.51E−010.98 (0.84–1.14)rs4406273HLA-B, HLA-C0.0110.0450.0105.86E−074.12 (2.26–7.51)6.13E−010.85 (0.46–1.59)rs13437088MICA0.2900.2780.2695.94E−010.94 (0.76–1.17)1.38E−010.90 (0.78–1.04)rs33980500TRAF3IP20.0170.0500.0219.39E−063.13 (1.84–5.32)2.96E−011.28 (0.80–2.05)rs582757TNFAIP30.0560.0600.0637.20E−011.08 (0.71–1.63)3.70E−011.13 (0.86–1.48)rs2451258TAGAP0.0290.0210.0213.14E−010.72 (0.37–1.38)1.05E−010.72 (0.48–1.07)rs2700987ELMO10.0940.1090.0942.87E−011.19 (0.86–1.63)9.86E−011.00 (0.81–1.25)rs11795343DDX580.2240.2410.2574.23E−011.10 (0.87–1.38)1.92E−021.19 (1.03–1.39)rs10979182KLF40.3990.4420.4168.14E−021.19 (0.98–1.45)2.89E−011.07 (0.94–1.22)rs1250546ZMIZ10.4730.4170.4222.43E−020.80 (0.66–0.97)1.65E−030.82 (0.72–0.93)rs645078RPS6KA4, PRDX50.2390.2340.2398.33E−010.98 (0.78–1.23)9.94E−011.00 (0.86–1.16)rs4561177ZC3H12C0.3650.3710.3828.24E−011.02 (0.84–1.25)2.95E−011.07 (0.94–1.22)rs3802826ETS10.2690.3010.2921.45E−011.17 (0.95–1.45)1.12E−011.12 (0.97–1.29)rs2066819STAT2, IL23A0.0460.0270.0376.15E−020.58 (0.33–1.03)2.01E−010.81 (0.59–1.12)rs8016947NFKBIA0.4790.4540.4713.15E−010.90 (0.74–1.10)6.23E−010.97 (0.85–1.10)rs367569PRM3, SOCS10.0940.0810.0993.59E−010.85 (0.60–1.21)5.87E−011.06 (0.86–1.31)rs12445568PRSS53, FBXL190.0850.0930.0665.77E−011.10 (0.78–1.54)2.60E−020.76 (0.60–0.97)rs28998802NOS20.0090.0100.0098.09E−011.13 (0.41–3.11)9.97E−011.00 (0.50–1.99)rs963986PTRF, STAT3, STAT5A/B0.3720.4420.3774.18E−031.33 (1.09–1.63)7.89E−011.02 (0.89–1.16)rs11652075CARD140.4090.4400.4132.17E−011.13 (0.93–1.38)7.98E−011.02 (0.89–1.16)rs545979POL1, STARD6, MBD20.0240.0290.0225.31E−011.21 (0.67–2.19)6.97E−010.92 (0.60–1.40)rs892085ILF3, CARM10.2750.2850.2606.54E−011.05 (0.85–1.30)2.92E−010.93 (0.80–1.07)rs1056198RNF1140.3150.3080.3417.51E−010.97 (0.78–1.19)8.67E−021.13 (0.98–1.29)rs4821124UBE2L30.3570.3750.3714.40E−011.08 (0.88–1.33)3.80E−011.06 (0.93–1.21) Open table in a new tab A recent GWAS of childhood-onset AD showed the genetic relationship between AD and psoriasis [[4]Weidinger S. Willis-Owen S.A. Kamatani Y. Baurecht H. Morar N. Liang L. et al.A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.Hum Mol Genet. 2013; 22: 4841-4856Crossref PubMed Scopus (143) Google Scholar]. The study examined SNPs previously shown to associate with psoriasis by a GWAS, and approximately two-thirds of those associated variants exhibited opposite risk profiles for AD versus psoriasis. The most significant association with AD in that study was observed at SNP rs1295685 in the IL13 locus at a genome-wide level that exhibited opposing effects in AD and psoriasis. In this study, we observed marginal associations between AD and the two susceptibility SNPs for psoriasis, IL13 (rs1295685, P = 3.5 × 10−3) and ZMIZ1 (rs1250546, P = 1.7 × 10−3), in the opposite and same direction, respectively. ZMIZ1 encodes a member of the PIAS (protein inhibitor of activated STAT) family of proteins that regulates the activity of several transcription factors [[10]Li X. Thyssen G. Beliakoff J. Sun Z. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity.J Biol Chem. 2006; 281: 23748-23756Crossref PubMed Scopus (50) Google Scholar]. The IL13 and ZMIZ1 loci might contain common genetic factors shared by these two common skin diseases.Our data strongly suggests the importance of the TNIP, IL12B, TRAF3IP2 loci and the MHC class I region in the susceptibility to PsV in the Japanese population. However, there are two limitations in our study. First, the sample size was relatively small. Second, we conducted the validation study using only SNPs reported in previous GWASs of psoriasis. Therefore, the associations of the other SNPs within the susceptibility loci remain unclear and further studies are necessary to achieve better understanding the genetic components of these chronic inflammatory skin diseases. Psoriasis is a chronic inflammatory skin disease caused by interplay between genetic and environmental factors, and psoriasis vulgaris (PsV) is the most common form of the disease [[1]Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2135) Google Scholar]. Recent genome-wide association studies (GWASs) and meta-analysis of GWAS of psoriasis in European individuals have identified a total of 36 susceptibility loci at a genome-wide level of significance (P < 5 × 10−8) [[2]Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. et al.Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (680) Google Scholar]. Conditional analysis of the 36 loci was also conducted and further identified five additional SNPs, rs2111485, rs2910686, rs4379175, rs13437088 and rs12720356 with genome-wide significance. We conducted a validation study of these 41 SNPs among the 36 loci in Japanese patients with PsV. Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and recent linkage and association studies have identified overlapping susceptibility loci of psoriasis and AD [3Elder J.T. Bruce A.T. Gudjonsson J.E. Johnston A. Stuart P.E. Tejasvi T. et al.Molecular dissection of psoriasis: integrating genetics and biology.J Invest Dermatol. 2010; 130: 1213-1226Crossref PubMed Scopus (232) Google Scholar, 4Weidinger S. Willis-Owen S.A. Kamatani Y. Baurecht H. Morar N. Liang L. et al.A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.Hum Mol Genet. 2013; 22: 4841-4856Crossref PubMed Scopus (143) Google Scholar]. Since identification of shared genetic components helps to highlight the key molecular pathways involved in chronic inflammatory skin diseases, we also explored the association of these 41 SNPs in Japanese patients with AD. We recruited a total of 259 patients with PsV diagnosed by clinical and histopathological findings (median age 53, 11–85 years, male:female ratio = 2.4:1.0) and a total of 999 patients with AD diagnosed according to the criteria of Hanifin and Rajka (median age 29, 3–77 years, male:female ratio = 1.3:1.0). As controls, 938 individuals who had never been diagnosed with AD or PsV were recruited from Fukui University and Miyatake Clinic (median age 50, 20–75 years, male:female ratio = 2.0:1.0). All individuals were unrelated Japanese and gave written informed consent to participate in the study. The study was approved by the ethical committees of the hospitals involved, the University of Tokyo, the Jikei University School of Medicine, Fukui University, Miyatake Clinic and the Institute of Physical and Chemical Research (RIKEN). Genomic DNA was prepared in accordance with standard protocols. We selected a total of 41 SNPs achieving genome-wide significance in a previous meta-analysis of GWASs [[2]Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. et al.Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (680) Google Scholar]. SNPs were genotyped by using the multiplex PCR-based Invader assay (Third Wave Japan). We calculated allele frequencies and tested agreement with Hardy–Weinberg equilibrium using a χ2 goodness of fit test as described [[5]Hirota T. Takahashi A. Kubo M. Tsunoda T. Tomita K. Sakashita M. et al.Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population.Nat Genet. 2012; 44: 1222-1226Crossref PubMed Scopus (246) Google Scholar], and no SNP was excluded from the analysis. Among 41 SNPs, four (rs9988642, rs12188300, rs34536443 and rs12720356) were found to be monomorphic in this study. We compared differences in the allele frequencies of the 37 polymorphisms between case and control subjects by using a contingency χ2 test or Fisher's exact test, and calculated odds ratios (ORs) with 95 percent confidence intervals (95% CI). We then applied Bonferroni corrections, the multiplication of P values by the number SNPs assessed (n = 37). Statistical significance was set at P < 0.05. All genotype frequencies and statistical results are shown in Table 1 and Supplementary Tables S1 and S2. We found significant associations with PsV in four SNPs, TNIP1 (rs2233278, P = 3.5 × 10−8), IL12B (rs4379175, P = 1.2 × 10−6), the MHC class I region (rs4406273, P = 5.9 × 10−7) and TRAF3IP2 (rs33980500, P = 9.4 × 10−6), after Bonferroni correction for 37 tests with P < 1.4 × 10−3 (0.05/37) (Table 1). The direction of associations of susceptibility to PsV was similar to that in the recent study [[2]Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. et al.Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (680) Google Scholar], and confirmed previous Japanese studies that have shown significant associations with IL12B [[6]Tsunemi Y. Saeki H. Nakamura K. Sekiya T. Hirai K. Fujita H. et al.Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.J Dermatol Sci. 2002; 30: 161-166Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar], TRAF3IP2 [[7]Hayashi M. Hirota T. Saeki H. Nakagawa H. Ishiuji Y. Matsuzaki H. et al.Genetic polymorphism in the TRAF3IP2 gene is associated with psoriasis vulgaris in a Japanese population.J Dermatol Sci. 2014; 73: 264-265Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar] and the MHC class I region [[8]Oka A. Tamiya G. Tomizawa M. Ota M. Katsuyama Y. Makino S. et al.Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene.Hum Mol Genet. 1999; 8: 2165-2170Crossref PubMed Scopus (149) Google Scholar]. The strongest association was observed in Japanese patients with PsV for the first time at TNIP for SNP rs2233278, and TNIP encodes ABIN-1, an A20-binding protein that links A20 to NEMO/IKKγ and results in inhibition of NF-κB by facilitation of A20-mediated deubiquitination of NEMO/IKKγ [[9]Mauro C. Pacifico F. Lavorgna A. Mellone S. Iannetti A. Acquaviva R. et al.ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-κB.J Biol Chem. 2006; 281: 18482-18488Crossref PubMed Scopus (202) Google Scholar]. A recent GWAS of childhood-onset AD showed the genetic relationship between AD and psoriasis [[4]Weidinger S. Willis-Owen S.A. Kamatani Y. Baurecht H. Morar N. Liang L. et al.A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.Hum Mol Genet. 2013; 22: 4841-4856Crossref PubMed Scopus (143) Google Scholar]. The study examined SNPs previously shown to associate with psoriasis by a GWAS, and approximately two-thirds of those associated variants exhibited opposite risk profiles for AD versus psoriasis. The most significant association with AD in that study was observed at SNP rs1295685 in the IL13 locus at a genome-wide level that exhibited opposing effects in AD and psoriasis. In this study, we observed marginal associations between AD and the two susceptibility SNPs for psoriasis, IL13 (rs1295685, P = 3.5 × 10−3) and ZMIZ1 (rs1250546, P = 1.7 × 10−3), in the opposite and same direction, respectively. ZMIZ1 encodes a member of the PIAS (protein inhibitor of activated STAT) family of proteins that regulates the activity of several transcription factors [[10]Li X. Thyssen G. Beliakoff J. Sun Z. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity.J Biol Chem. 2006; 281: 23748-23756Crossref PubMed Scopus (50) Google Scholar]. The IL13 and ZMIZ1 loci might contain common genetic factors shared by these two common skin diseases. Our data strongly suggests the importance of the TNIP, IL12B, TRAF3IP2 loci and the MHC class I region in the susceptibility to PsV in the Japanese population. However, there are two limitations in our study. First, the sample size was relatively small. Second, we conducted the validation study using only SNPs reported in previous GWASs of psoriasis. Therefore, the associations of the other SNPs within the susceptibility loci remain unclear and further studies are necessary to achieve better understanding the genetic components of these chronic inflammatory skin diseases. We thank all the individuals who participated in the study. We also thank M.T. Shimizu, H. Sekiguchi, A.I. Jodo, N. Kawaraichi and the technical staff of the Center for Genomic Medicine for providing technical assistance and K. Barrymore for proofreading this manuscript. This work was supported by Health Science Research Grants from the Ministry of Health, Welfare and Labor of Japan and the Ministry of Education, Culture, Sports, Science and Technology, Japan. Appendix A. Supplementary dataThe following are supplementary data to this article: Download .docx (.2 MB) Help with docx files The following are supplementary data to this article: Download .docx (.2 MB) Help with docx files

The authors regret that there was an error in the ratios on page 148, the first sentence in the second paragraph: [Incorrect] We recruited a total of 236 patients with PsV (mean age 53, 11–85 years, male:female ratio = 1.0:2.8), and all subjects were diagnosed by clinical and histopathological findings. A total of 916 patients with AD (mean age 30, 3–77 years, male:female ratio = 1.0:2.2) and 844 controls (mean age 50, 20–75 years, male:female ratio = 1.0:1.3) were recruited as described [7]. [Correct] We recruited a total of 236 patients with PsV (mean age 53, 11–85 years, male:female ratio = 2.2:1.0), and all subjects were diagnosed by clinical and histopathological findings. A total of 916 patients with AD (mean age 30, 3–77 years, male:female ratio = 1.3:1.0) and 844 controls (mean age 50, 20–75 years, male:female ratio = 2.8:1.0) were recruited as described [7]. The authors would like to apologise for any inconvenience caused. Genetic polymorphisms in the IL22 gene are associated with psoriasis vulgaris in a Japanese populationJournal of Dermatological ScienceVol. 71Issue 2PreviewPsoriasis vulgaris (PsV) is an inflammatory skin disease histologically characterized by epidermal hyperplasia, inflammatory cell infiltration and vascular changes in which T-lymphocytes and associated cytokines play a central role [1]. A dysregulated cutaneous immune response occurs in genetically susceptible individuals and the features of inflammation are characterized by tumor necrosis factor (TNF)-α dependence and exaggerated helper T cell 1 (Th1) and 17 (Th17) activation. Interleukin (IL)-22 is an IL-10 family cytokine member produced by Th17 cells and plays a role in the promotion of inflammation and tissue repair at barrier surfaces [2]. Full-Text PDF