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3.  CTNNA3 (α-Catenin) Gene Variants Are Associated With Diisocyanate Asthma: A Replication Study in a Caucasian Worker Population 
Toxicological Sciences  2012;131(1):242-246.
Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, and rs4378283) associated with diisocyanate-induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5′ nuclease PCR assay collected from 410 diisocyanate-exposed and predominantly Canadian workers including 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA−); and 147 hexamethylene diisocyanate–exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA+ when compared with AWs but not in comparison with DA− workers (p ≤ 0.05). After adjusting for potentially confounding variables of age, smoking status, and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs (OR = 9.05 [95% CI: 1.69, 48.54] and OR = 6.82 [95% CI: 1.65, 28.24], respectively). In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of catenins in the disease process.
doi:10.1093/toxsci/kfs272
PMCID: PMC3537126  PMID: 22977168
diisocyanate asthma; CTNNA3; alpha-T catenin; occupational asthma
4.  Diagnosis and Management of Grain-Induced Asthma 
Grain-induced asthma is a frequent occupational allergic disease mainly caused by inhalation of cereal flour or powder. The main professions affected are bakers, confectioners, pastry factory workers, millers, farmers, and cereal handlers. This disorder is usually due to an IgE-mediated allergic response to inhalation of cereal flour proteins. The major causative allergens of grain-related asthma are proteins derived from wheat, rye and barley flour, although baking additives, such as fungal α-amylase are also important. This review deals with the current diagnosis and treatment of grain-induced asthma, emphasizing the role of cereal allergens as molecular tools to enhance diagnosis and management of this disorder. Asthma-like symptoms caused by endotoxin exposure among grain workers are beyond the scope of this review. Progress is being made in the characterization of grain and bakery allergens, particularly cereal-derived allergens, as well as in the standardization of allergy tests. Salt-soluble proteins (albumins plus globulins), particularly members of the α-amylase/trypsin inhibitor family, thioredoxins, peroxidase, lipid transfer protein and other soluble enzymes show the strongest IgE reactivities in wheat flour. In addition, prolamins (not extractable by salt solutions) have also been claimed as potential allergens. However, the large variability of IgE-binding patterns of cereal proteins among patients with grain-induced asthma, together with the great differences in the concentrations of potential allergens observed in commercial cereal extracts used for diagnosis, highlight the necessity to standardize and improve the diagnostic tools. Removal from exposure to the offending agents is the cornerstone of the management of grain-induced asthma. The availability of purified allergens should be very helpful for a more refined diagnosis, and new immunomodulatory treatments, including allergen immunotherapy and biological drugs, should aid in the management of patients with this disorder.
doi:10.4168/aair.2013.5.6.348
PMCID: PMC3810540  PMID: 24179680
Baker's asthma; cereals; wheat allergens; soya flour; fungal enzymes; allergen immunotherapy
5.  Genetic Variants in Antioxidant Genes Are Associated With Diisocyanate-Induced Asthma 
Toxicological Sciences  2012;129(1):166-173.
Diisocyanates are a common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants of antioxidant defense genes, glutathione S-transferases (GSTM1, GSTT1, GSTM3, GSTP1), manganese superoxide dismutase (SOD2), and microsomal epoxide hydrolase (EPHX1) are associated with increased susceptibility to diisocyanate-induced asthma (DA). The main study population consisted of 353 Caucasian French-Canadians from among a larger sample of 410 diisocyanate-exposed workers in three groups: workers with specific inhalation challenge (SIC) confirmed DA (DA+, n = 95); symptomatic diisocyanate workers with a negative SIC (DA−, n = 116); and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5′-nuclease PCR assay. The SOD2 rs4880, GSTP1 rs1695, and EPHX1 rs2740171 variants were significantly associated with DA in both univariate and multivariate analyses. In the first logistic regression model comparing DA+ and DA− groups, SOD2 rs4880, GSTM1 (null), GSTP1 rs762803, and EPHX1 rs2854450 variants were associated with DA (p = 0.004, p = 0.047, p = 0.021, p <0.001, respectively). Genotype combinations GSTT1*GSTP1 rs762803, GSTM1*EPHX1 rs2854450, EPHX1 rs2740168*EPHX1 rs1051741, and GSTP1 rs762803*EPHX1 rs2740168 were also associated with DA in this model (p = 0.027, p = 0.002, p = 0.045, p = 0.044, respectively). The GSTP1 rs1695 and EPHX1 rs1051741 and rs2740171 variants showed an association with DA in the second model comparing DA+ and AW groups (p = 0.040, p = 0.019, p = 0.002, respectively). The GSTM3 rs110913*EPHX1 rs1051741 genotype combination was also associated with DA under this model (p = 0.042). The results suggest that variations in SOD2, GST, and EPHX1 genes and their interactions contribute to DA susceptibility.
doi:10.1093/toxsci/kfs183
PMCID: PMC3499076  PMID: 22610343
diisocyanates;  occupational asthma;  antioxidant;  genetics;  single-nucleotide polymorphism.
6.  Research needs in allergy: an EAACI position paper, in collaboration with EFA 
Papadopoulos, Nikolaos G | Agache, Ioana | Bavbek, Sevim | Bilo, Beatrice M | Braido, Fulvio | Cardona, Victoria | Custovic, Adnan | deMonchy, Jan | Demoly, Pascal | Eigenmann, Philippe | Gayraud, Jacques | Grattan, Clive | Heffler, Enrico | Hellings, Peter W | Jutel, Marek | Knol, Edward | Lötvall, Jan | Muraro, Antonella | Poulsen, Lars K | Roberts, Graham | Schmid-Grendelmeier, Peter | Skevaki, Chrysanthi | Triggiani, Massimo | vanRee, Ronald | Werfel, Thomas | Flood, Breda | Palkonen, Susanna | Savli, Roberta | Allegri, Pia | Annesi-Maesano, Isabella | Annunziato, Francesco | Antolin-Amerigo, Dario | Apfelbacher, Christian | Blanca, Miguel | Bogacka, Ewa | Bonadonna, Patrizia | Bonini, Matteo | Boyman, Onur | Brockow, Knut | Burney, Peter | Buters, Jeroen | Butiene, Indre | Calderon, Moises | Cardell, Lars Olaf | Caubet, Jean-Christoph | Celenk, Sevcan | Cichocka-Jarosz, Ewa | Cingi, Cemal | Couto, Mariana | deJong, Nicolette | Del Giacco, Stefano | Douladiris, Nikolaos | Fassio, Filippo | Fauquert, Jean-Luc | Fernandez, Javier | Rivas, Montserrat Fernandez | Ferrer, Marta | Flohr, Carsten | Gardner, James | Genuneit, Jon | Gevaert, Philippe | Groblewska, Anna | Hamelmann, Eckard | Hoffmann, Hans Jürgen | Hoffmann-Sommergruber, Karin | Hovhannisyan, Lilit | Hox, Valérie | Jahnsen, Frode L | Kalayci, Ömer | Kalpaklioglu, Ayse Füsun | Kleine-Tebbe, Jörg | Konstantinou, George | Kurowski, Marcin | Lau, Susanne | Lauener, Roger | Lauerma, Antti | Logan, Kirsty | Magnan, Antoine | Makowska, Joanna | Makrinioti, Heidi | Mangina, Paraskevi | Manole, Felicia | Mari, Adriano | Mazon, Angel | Mills, Clare | Mingomataj, ErvinÇ | Niggemann, Bodo | Nilsson, Gunnar | Ollert, Markus | O'Mahony, Liam | O'Neil, Serena | Pala, Gianni | Papi, Alberto | Passalacqua, Gianni | Perkin, Michael | Pfaar, Oliver | Pitsios, Constantinos | Quirce, Santiago | Raap, Ulrike | Raulf-Heimsoth, Monika | Rhyner, Claudio | Robson-Ansley, Paula | Alves, Rodrigo Rodrigues | Roje, Zeljka | Rondon, Carmen | Rudzeviciene, Odilija | Ruëff, Franziska | Rukhadze, Maia | Rumi, Gabriele | Sackesen, Cansin | Santos, Alexandra F | Santucci, Annalisa | Scharf, Christian | Schmidt-Weber, Carsten | Schnyder, Benno | Schwarze, Jürgen | Senna, Gianenrico | Sergejeva, Svetlana | Seys, Sven | Siracusa, Andrea | Skypala, Isabel | Sokolowska, Milena | Spertini, Francois | Spiewak, Radoslaw | Sprikkelman, Aline | Sturm, Gunter | Swoboda, Ines | Terreehorst, Ingrid | Toskala, Elina | Traidl-Hoffmann, Claudia | Venter, Carina | Vlieg-Boerstra, Berber | Whitacker, Paul | Worm, Margitta | Xepapadaki, Paraskevi | Akdis, Cezmi A
In less than half a century, allergy, originally perceived as a rare disease, has become a major public health threat, today affecting the lives of more than 60 million people in Europe, and probably close to one billion worldwide, thereby heavily impacting the budgets of public health systems. More disturbingly, its prevalence and impact are on the rise, a development that has been associated with environmental and lifestyle changes accompanying the continuous process of urbanization and globalization. Therefore, there is an urgent need to prioritize and concert research efforts in the field of allergy, in order to achieve sustainable results on prevention, diagnosis and treatment of this most prevalent chronic disease of the 21st century.
The European Academy of Allergy and Clinical Immunology (EAACI) is the leading professional organization in the field of allergy, promoting excellence in clinical care, education, training and basic and translational research, all with the ultimate goal of improving the health of allergic patients. The European Federation of Allergy and Airways Diseases Patients’ Associations (EFA) is a non-profit network of allergy, asthma and Chronic Obstructive Pulmonary Disorder (COPD) patients’ organizations. In support of their missions, the present EAACI Position Paper, in collaboration with EFA, highlights the most important research needs in the field of allergy to serve as key recommendations for future research funding at the national and European levels.
Although allergies may involve almost every organ of the body and an array of diverse external factors act as triggers, there are several common themes that need to be prioritized in research efforts. As in many other chronic diseases, effective prevention, curative treatment and accurate, rapid diagnosis represent major unmet needs. Detailed phenotyping/endotyping stands out as widely required in order to arrange or re-categorize clinical syndromes into more coherent, uniform and treatment-responsive groups. Research efforts to unveil the basic pathophysiologic pathways and mechanisms, thus leading to the comprehension and resolution of the pathophysiologic complexity of allergies will allow for the design of novel patient-oriented diagnostic and treatment protocols. Several allergic diseases require well-controlled epidemiological description and surveillance, using disease registries, pharmacoeconomic evaluation, as well as large biobanks. Additionally, there is a need for extensive studies to bring promising new biotechnological innovations, such as biological agents, vaccines of modified allergen molecules and engineered components for allergy diagnosis, closer to clinical practice. Finally, particular attention should be paid to the difficult-to-manage, precarious and costly severe disease forms and/or exacerbations. Nonetheless, currently arising treatments, mainly in the fields of immunotherapy and biologicals, hold great promise for targeted and causal management of allergic conditions. Active involvement of all stakeholders, including Patient Organizations and policy makers are necessary to achieve the aims emphasized herein.
doi:10.1186/2045-7022-2-21
PMCID: PMC3539924  PMID: 23121771
Allergy; Allergic diseases; Policy; Research needs; Research funding; Europe
7.  Measurement of asthma control according to global initiative for asthma guidelines: a comparison with the asthma control questionnaire 
Respiratory Research  2012;13(1):50.
Introduction
Asthma Control Questionnaire (ACQ) is a validated tool to measure asthma control. Cut-off points that best discriminate “well-controlled” or “not well-controlled” asthma have been suggested from the analysis of a large randomized clinical trial but they may not be adequate for daily clinical practice.
Aims
To establish cut-off points of the ACQ that best discriminate the level of control according to Global Initiative for Asthma (GINA) 2006 guidelines in patients with asthma managed at Allergology and Pulmonology Departments as well as Primary Care Centers in Spain.
Patients and methods
An epidemiological descriptive study, with prospective data collection. Asthma control following GINA-2006 classification and 7-item ACQ was assessed. The study population was split in two parts: 2/3 for finding the cut-off points (development population) and 1/3 for validating the results (validation population).
Results
A total of 1,363 stable asthmatic patients were included (mean age 38 ± 14 years, 60.3% women; 69.1% non-smokers). Patient classification according to GINA-defined asthma control was: controlled 13.6%, partially controlled 34.2%, and uncontrolled 52.3%. The ACQ cut-off points that better agreed with GINA-defined asthma control categories were calculated using receiver operating curves (ROC). The analysis showed that ACQ < 0.5 was the optimal cut-off point for “controlled asthma” (sensitivity 74.1%, specificity 77.5%) and 1.00 for “uncontrolled asthma” (sensitivity 73%, specificity 88.2%). Kappa index between GINA categories and ACQ was 0.62 (p < 0.001).
Conclusion
The ACQ cut-off points associated with GINA-defined asthma control in a real-life setting were <0.5 for controlled asthma and ≥1 for uncontrolled asthma.
doi:10.1186/1465-9921-13-50
PMCID: PMC3462124  PMID: 22726416
Asthma control; GINA guidelines; Asthma control questionnaire; Validation study
8.  Hexamethylene Diisocyanate Asthma is Associated with Genetic Polymorphisms of CD14, IL-13, and IL-4RA 
doi:10.1016/j.jaci.2011.03.007
PMCID: PMC3164978  PMID: 21489615
diisocyanate-induced asthma; occupational asthma; genetics of asthma; IL4RA (I50V); IL13 (R110Q); CD14 (C159T
9.  Suppressors of Cytokine Signaling 3 Expression in Eosinophils: Regulation by PGE2 and Th2 Cytokines 
Asthma and nonasthmatic eosinophilic bronchitis (NAEB) are respiratory disorders characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS) proteins play an important role in Th2-mediated allergic responses through control of the balance between Th1 and Th2 cells, particularly, SOCS3 and SOCS5. The aim of this study was to analyze SOCS expression in human peripheral blood eosinophils from patients with asthma, NAEB and healthy controls. SOCS expression in eosinophils from subjects was demonstrated by different techniques. Results showed that expression of SOCS3 in eosinophils and CD4 T cells from patients was higher than in healthy subjects. In addition, we demonstrated that prostaglandin E2 (PGE2) and Th2 cytokines are able to upregulate SOCS3 production in eosinophils and attenuate its degranulation. In conclusion, eosinophils are able to transcribe and translate SOCS3 protein and can contribute to the regulation of the Th1/Th2 balance through SOCS3 production.
doi:10.1155/2011/917015
PMCID: PMC3135166  PMID: 21765854
10.  Overall asthma control achieved with budesonide/formoterol maintenance and reliever therapy for patients on different treatment steps 
Respiratory Research  2011;12(1):38.
Background
Adjusting medication for uncontrolled asthma involves selecting one of several options from the same or a higher treatment step outlined in asthma guidelines. We examined the relative benefit of introducing budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (Symbicort SMART® Turbuhaler®) in patients previously prescribed treatments from Global Initiative for Asthma (GINA) Steps 2, 3 or 4.
Methods
This is a post hoc analysis of the results of five large clinical trials (>12000 patients) comparing BUD/FORM maintenance and reliever therapy with other treatments categorised by treatment step at study entry. Both current clinical asthma control during the last week of treatment and exacerbations during the study were examined.
Results
At each GINA treatment step, the proportion of patients achieving target levels of current clinical control were similar or higher with BUD/FORM maintenance and reliever therapy compared with the same or a higher fixed maintenance dose of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) (plus short-acting β2-agonist [SABA] as reliever), and rates of exacerbations were lower at all treatment steps in BUD/FORM maintenance and reliever therapy versus same maintenance dose ICS/LABA (P < 0.01) and at treatment Step 4 versus higher maintenance dose ICS/LABA (P < 0.001). BUD/FORM maintenance and reliever therapy also achieved significantly higher rates of current clinical control and significantly lower exacerbation rates at most treatment steps compared with a higher maintenance dose ICS + SABA (Steps 2-4 for control and Steps 3 and 4 for exacerbations). With all treatments, the proportion of patients achieving current clinical control was lower with increasing treatment steps.
Conclusions
BUD/FORM maintenance and reliever therapy may be a preferable option for patients on Steps 2 to 4 of asthma guidelines requiring a more effective treatment and, compared with other fixed dose alternatives, is most effective in the higher treatment steps.
doi:10.1186/1465-9921-12-38
PMCID: PMC3082240  PMID: 21463522
11.  EAACI position paper on occupational rhinitis 
Respiratory Research  2009;10(1):16.
The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.
doi:10.1186/1465-9921-10-16
PMCID: PMC2654869  PMID: 19257881

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