Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Autologous fat transplantation alters gene expression patterns related to inflammation and hypoxia in the irradiated human breast.

BACKGROUND: Radiation-induced fibrosis, an adverse effect of breast cancer treatment, is associated with functional and cosmetic impairment as well as surgical complications. Clinical reports suggest improvement following autologous fat transplantation, but the mechanisms underlying this effect are unknown. A global gene expression analysis was undertaken to identify genetic pathways dysregulated by radiation and evaluate the impact of autologous fat transplantation on gene expression. METHODS: Adipose tissue biopsies were taken synchronously from irradiated and contralateral non-irradiated breasts, before and 1 year after autologous fat transplantation. Whole-genome gene expression analyses were performed, and Hallmark gene set analysis used to explore the effect of radiotherapy and autologous fat transplantation on gene expression. RESULTS: Forty microarrays were analysed, using bilateral biopsies taken from ten patients before and after autologous fat transplantation. Forty-five pathways were identified among the 3000 most dysregulated transcripts after radiotherapy in irradiated compared with non-irradiated breast (P ≤ 0·023; false discovery rate (FDR) no higher than 0·026). After autologous fat transplantation, 575 of the 3000 genes were again altered. Thirteen pathways (P ≤ 0·013; FDR 0·050 or less) were identified; the top two canonical pathways were interferon-γ response and hypoxia. Correlative immunohistochemistry showed increased macrophage recruitment in irradiated tissues. CONCLUSION: The present findings contribute to understanding of how autologous fat transplantation can ameliorate radiation-induced fibrosis. This further supports the use of autologous fat transplantation in the treatment of radiation-induced fibrosis. Surgical relevance Clinical studies have indicated that autologous fat transplantation (AFT) stimulates regression of chronic inflammation and fibrosis caused by radiotherapy in skin and subcutaneous fat. However, there is a paucity of biological evidence and the underlying processes are poorly understood. Human data are scarce, whereas experimental studies have focused mainly either on the effect of irradiation or AFT alone. The present results indicate that radiotherapy causes dysregulated gene expression in fibrosis-related pathways in adipose tissues in humans. They also show that AFT can cause a reversal of this, with several dysregulated genes returning to nearly normal expression levels. The study provides biological evidence for the impact of AFT on radiation-induced dysregulated gene expression in humans. It supports the use of AFT in the treatment of radiation-induced fibrosis, associated with severe morbidity and surgical challenges.

Environmental peanut exposure increases the risk of peanut sensitization in high-risk children.

BACKGROUND: High household peanut consumption is associated with the development of peanut allergy, especially when peanut allergic cases are compared against atopic controls; thus, environmental peanut exposure (EPE) may be a risk factor for peanut sensitization and allergy. In this study, we explored the relationship between EPE and school-age peanut sensitization in a population-based cohort. METHODS: Maternal bed dust was collected postnatally, and EPE was quantified using a polyclonal peanut ELISA. Peanut sensitization was assessed by specific IgE to peanut extract and sIgE to peanut protein component allergens Ara h 1, 2 or 3 ≥ 0.35kU/L (primary peanut sensitization). Initial nested case-control analysis was performed comparing peanut-sensitized cases against high-risk controls (matched for parental atopy) (n = 411) using a conditional regression analysis. This was followed by whole cohort analysis (n = 1878) comparing EPE against peanut sIgE sensitization at ages 4 and 8 years using generalized estimating equations and against primary peanut sensitization at age 8 years using a logistic regression model. Finally, a subgroup analysis was performed comparing the impact of EPE in peanut-sensitized vs egg-sensitized, peanut-tolerant individuals using logistic regression analysis. Levels of EPE were compared between groups using the Mann-Whitney U test. RESULTS: In the nested case-control analysis, a higher level of EPE around birth was associated with peanut-specific IgE sensitization at age 4 years (OR=1.41, 95% CI:1.05-1.90) and primary peanut sensitization at age 8 years (OR=2.11, 95% CI:1.38-3.22) compared against high-risk controls. When the whole BAMSE cohort was assessed, EPE was no longer associated with peanut sensitization; however, on subgroup analysis, EPE was associated with primary peanut sensitization when compared against egg-sensitized peanut-tolerant controls with an adjusted odds ratio of 1.44 per unit EPE (95% CI:1.06-1.94). There was no significant interaction between EPE and FLG loss-of-function mutations, egg sensitization at age 4 years, infantile eczema or parental atopy on peanut sensitization. CONCLUSIONS: Higher levels of environmental exposure to peanut in the first few months of life appear to increase the probability of developing school-age peanut sensitization in atopic children (based on egg sensitization and parental atopy).

The asthma-rhinitis multimorbidity is associated with IgE polysensitization in adolescents and adults.

BACKGROUND: Children with multimorbid asthma and rhinitis show IgE polysensitization to several allergen sources. This association remains poorly studied in adolescents and adults using defined allergen molecules. We investigated IgE sensitization patterns towards a broad panel of aeroallergen components in adults and adolescents with a focus on individuals with asthma and rhinitis multimorbidity. METHODS: IgE reactivity to 64 micro-arrayed aeroallergen molecules was determined with the MeDALL-chip in samples from the French EGEA study (n = 840, age = 40.7 ± 17.1) and the Swedish population-based birth cohort BAMSE (n = 786, age = 16 ± 0.26). The age- and sex-adjusted associations between the number of IgE-reactive allergen molecules (≥0.3 ISU) and the asthma-rhinitis phenotypes were assessed using a negative binomial model. RESULTS: Groups representing 4 phenotypes were identified: no asthma-no rhinitis (A-R-; 30% in EGEA and 54% in BAMSE), asthma alone (A+R-; 11% and 8%), rhinitis alone (A-R+; 15% and 24%) and asthma-rhinitis (A+R+; 44% and 14%). The numbers of IgE-reactive aeroallergen molecules significantly differed between phenotypes (median in A-R-, A+R-, A-R+ and A+R+: 0, 1, 2 and 7 in EGEA and 0, 0, 3 and 5 in BAMSE). As compared to A-R- subjects, the adjusted ratio of the mean number of IgE-reactive molecules was higher in A+R+ than in A+R- or A-R+ (10.0, 5.4 and 5.0 in EGEA and 7.2, 0.7 and 4.8 in BAMSE). CONCLUSION: The A+R+ phenotype combined the sensitization pattern of both the A-R+ and A+R- phenotypes. This multimorbid polysensitized phenotype seems to be generalizable to various ages and allergenic environments and may be associated with specific mechanisms.

The urgent need for a harmonized severity scoring system for acute allergic reactions.

The accurate assessment and communication of the severity of acute allergic reactions are important to patients, clinicians, researchers, the food industry, and public health and regulatory authorities. Severity has different meanings to different stakeholders with patients and clinicians rating the significance of particular symptoms very differently. Many severity scoring systems have been generated, most focusing on the severity of reactions following exposure to a limited group of allergens. They are heterogeneous in format, none has used an accepted developmental approach, and none has been validated. Their wide range of outcome formats has led to difficulties with interpretation and application. Therefore, there is a persisting need for an appropriately developed and validated severity scoring system for allergic reactions that work across the range of allergenic triggers and address the needs of different stakeholder groups. We propose a novel approach to develop and then validate a harmonized scoring system for acute allergic reactions, based on a data-driven method that is informed by clinical and patient experience and other stakeholders' perspectives. We envisage two formats: (i) a numerical score giving a continuum from mild to severe reactions that are clinically meaningful and are useful for allergy healthcare professionals and researchers, and (ii) a three-grade-based ordinal format that is simple enough to be used and understood by other professionals and patients. Testing of reliability and validity of the new approach in a range of settings and populations will allow eventual implementation of a standardized scoring system in clinical studies and routine practice.

Developments in the field of allergy in 2016 through the eyes of Clinical and Experimental Allergy.

In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2016. Experimental models of allergic disease, basic mechanisms, clinical mechanisms, allergens, asthma and rhinitis, and clinical allergy are all covered.

Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2016 revision

BACKGROUND: Allergic rhinitis (AR) affects 10% to 40% of the population. It reduces quality of life and school and work performance and is a frequent reason for office visits in general practice. Medical costs are large, but avoidable costs associated with lost work productivity are even larger than those incurred by asthma. New evidence has accumulated since the last revision of the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines in 2010, prompting its update. OBJECTIVE: We sought to provide a targeted update of the ARIA guidelines. METHODS: The ARIA guideline panel identified new clinical questions and selected questions requiring an update. We performed systematic reviews of health effects and the evidence about patients' values and preferences and resource requirements (up to June 2016). We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence-to-decision frameworks to develop recommendations. RESULTS: The 2016 revision of the ARIA guidelines provides both updated and new recommendations about the pharmacologic treatment of AR. Specifically, it addresses the relative merits of using oral H1-antihistamines, intranasal H1-antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists either alone or in combination. The ARIA guideline panel provides specific recommendations for the choice of treatment and the rationale for the choice and discusses specific considerations that clinicians and patients might want to review to choose the management most appropriate for an individual patient. CONCLUSIONS: Appropriate treatment of AR might improve patients' quality of life and school and work productivity. ARIA recommendations support patients, their caregivers, and health care providers in choosing the optimal treatment.

Validation of the MASK-rhinitis visual analogue scale on smartphone screens to assess allergic rhinitis control.

BACKGROUND: Visual Analogue Scale (VAS) is a validated tool to assess control in allergic rhinitis patients. OBJECTIVE: The aim of this study was to validate the use of VAS in the MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) app (Allergy Diary) on smartphones screens to evaluate allergic rhinitis symptoms and disease control. METHODS: Each user filled 4 different VAS measuring overall, nasal, ocular, and asthma symptoms at least once. Following COSMIN guidelines, we evaluated internal consistency, (Cronbach's alpha coefficient and test-retest), reliability (intraclass correlation coefficients), sensitivity, and acceptability of the MASK-Rhinitis VAS. RESULTS: Between 1 August 2015 and 31 July 2016, the app was used 14 612 times in 15 countries. A total of 1225 users used it more than once, during the evaluated period. The tool resulted to be statistically satisfactory, showing excellent internal consistency (Cronbach's test > 0.84, test-retest > 0.7), reliability (>0.9), and acceptability. In addition, the tool had a good sensitivity when users (n = 521) answered the VAS twice in less than 3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: The MASK-rhinitis VAS is a reliable and valid tool to assess allergic control on smartphone screens, at the population level.

Staphylococcus aureus enterotoxin sensitization is associated with allergic poly-sensitization and allergic multimorbidity in adolescents.

BACKGROUND: Staphylococcus aureus (S. aureus) carriage and sensitization to S. aureus enterotoxins (SEs) have been associated with allergic diseases. From the Tromsø Study Fit Futures 2, we have previously shown an association between S. aureus carriage and severe allergic disease and allergic multimorbidity. However, the role of S. aureus carriage and SE sensitization on allergic multimorbidity and allergic sensitization is unclear. OBJECTIVE: To study associations of both nasal S. aureus carriage and SE sensitization to allergic disease and allergic sensitization. METHODS: A cross-sectional study of a school-based cohort in late adolescence (aged 18-19 years: The Tromsø Study Fit Futures 2). Self-reported allergic diseases were assessed using the Mechanisms of the Development of ALLergy questionnaire (MeDALL). Participants were tested for nasal S. aureus carriage, serum total IgE and specific IgE to SEs, and food and inhalant allergens. RESULTS: A total of 868 participants were studied. Sensitization to at least one food or inhalant allergen was found in 319 of 765 (41.7%), and to at least one SE in 173 of 656 (26.2%) participants. SE sensitization, but not S. aureus carriage, was associated with poly-sensitization to food and inhalant allergens. SE-sensitized participants had higher median specific IgE to inhalant allergens (41.4 kUA /L, IQR 10.1-118.4) compared to non-SE-sensitized participants (18.0 kUA /L, IQR 5.5-48.6, P=.004), but not to food allergens. SE sensitization was associated with allergic multimorbidity. CONCLUSION: Sensitization to SEs may play a role in the development of allergen poly-sensitization and allergic multimorbidity.

Dietary total antioxidant capacity in early school age and subsequent allergic disease.

BACKGROUND: Dietary antioxidant intake has been hypothesized to influence the development of allergic diseases; however, few prospective studies have investigated this association. OBJECTIVE: Our aim was to study the association between total antioxidant capacity (TAC) of the diet at age 8 years and the subsequent development of asthma, rhinitis and sensitization to inhalant allergens between 8 and 16 years, and to assess potential effect modification by known risk factors. METHODS: A total of 2359 children from the Swedish birth cohort BAMSE were included. Dietary TAC at age 8 years was estimated by combining information on the child's diet the past 12 months from a food frequency questionnaire with a database of common foods analysed with the oxygen radical absorbance capacity method. Classification of asthma and rhinitis was based on questionnaires, and serum IgE antibodies were measured at 8 and 16 years. RESULTS: A statistically significant inverse association was observed between TAC of the diet and incident sensitization to inhalant allergens (adjusted odds ratio: 0.73, 95% confidence interval: 0.55-0.97 for the third compared to the first tertile, P-value for trend = 0.031). Effect modification by traffic-related air pollution exposure was observed, with a stronger association between dietary TAC and sensitization among children with low traffic-related air pollution exposure (P-value for interaction = 0.029). There was no evidence for effect modification by GSTP1 or TNF genotypes, although these results should be interpreted with caution. No clear associations were observed between TAC and development of rhinitis or asthma, although a significant inverse association was observed for allergic asthma (ORadj 0.57, 95% CI 0.34-0.94). CONCLUSIONS AND CLINICAL RELEVANCE: Higher TAC of the diet in early school age may decrease the risk of developing sensitization to inhalant allergens from childhood to adolescence. These findings indicate that implementing an antioxidant-rich diet in childhood may contribute to the prevention of allergic disease.

Google Trends terms reporting rhinitis and related topics differ in European countries.

Google Trends (GT) searches trends of specific queries in Google and reflects the real-life epidemiology of allergic rhinitis. We compared Google Trends terms related to allergy and rhinitis in all European Union countries, Norway and Switzerland from 1 January 2011 to 20 December 2016. The aim was to assess whether the same terms could be used to report the seasonal variations of allergic diseases. Using the Google Trend 5-year graph, an annual and clear seasonality of queries was found in all countries apart from Cyprus, Estonia, Latvia, Lithuania and Malta. Different terms were found to demonstrate seasonality depending on the country - namely 'hay fever', 'allergy' and 'pollen' - showing cultural differences. A single set of terms cannot be used across all European countries, but allergy seasonality can be compared across Europe providing the above three terms are used. Using longitudinal data in different countries and multiple terms, we identified an awareness-related spike of searches (December 2016).

Developments in the field of clinical allergy in 2015 through the eyes of Clinical and Experimental Allergy.

In the second of two papers, we describe developments in the field of clinical allergy as documented by Clinical and Experimental Allergy in 2015. Epidemiology, clinical allergy, asthma and rhinitis are all covered.

Anaphylaxis to foods in a population of adolescents: incidence, characteristics and associated risks.

BACKGROUND: Information about severe reactions to foods in adolescence is limited. OBJECTIVE: To describe reactions to foods, including anaphylaxis, with regard to incidence, characteristics and associated risks, among 16-year-olds (adolescents) in a large, population-based birth cohort. METHODS: Parent-reported questionnaire data from ages 2-3 months, and 1, 2 and 16 years were used (N = 3153). Anaphylaxis at age 16 years was defined per NIAID/FAAN criteria. Immunoglobulin E (IgE) antibodies to 14 common food and inhalant allergens were analysed at ages 4 (n = 2283) and 16 years (n = 2510). Among adolescents with food-related symptoms (FRS) and for whom blood was available (n = 221), 25 additional food allergen extracts or allergen components were analysed. Associations between reactions to foods, and sensitization and allergic multimorbidity were investigated. RESULTS: In the 12 months prior to the 16-year assessment, 8.5% of adolescents had FRS. This included 0.8% (n = 24) adolescents who were classified as having anaphylaxis, yielding an incidence rate of 761/100 000 person-years. One-third of adolescents accessed health care during anaphylaxis. Allergic multimorbidity in infancy, as well as sensitization to foods and airborne allergens at age 4 years, was associated with an increased risk for FRS in adolescence. Peanuts and tree nuts were the most common culprit foods for anaphylaxis, and fruits and vegetables for non-anaphylactic reactions. Adolescents with anaphylaxis were significantly more likely to be sensitized to storage proteins (Ara h 2, Cor a 9, Cor a 14) and to be polysensitized to foods (P < 0.001 vs. non-anaphylactic reactions). CONCLUSIONS AND CLINICAL RELEVANCE: The incidence of food-induced anaphylaxis during adolescence in our population-based birth cohort is higher than previously reported. Adolescents with anaphylaxis differ from adolescents with non-anaphylactic FRS with regard to culprit foods and sensitization. Adolescents with previous anaphylaxis are likely to be polysensitized to foods, particularly tree nut and peanut storage proteins, and which warrants consideration at follow-up.

Developments in the field of allergy mechanisms in 2015 through the eyes of Clinical & Experimental Allergy.

In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects.

Protein profiles of CCL5, HPGDS, and NPSR1 in plasma reveal association with childhood asthma.

Asthma is a common chronic childhood disease with many different phenotypes that need to be identified. We analyzed a broad range of plasma proteins in children with well-characterized asthma phenotypes to identify potential markers of childhood asthma. Using an affinity proteomics approach, plasma levels of 362 proteins covered by antibodies from the Human Protein Atlas were investigated in a total of 154 children with persistent or intermittent asthma and controls. After screening, chemokine ligand 5 (CCL5) hematopoietic prostaglandin D synthase (HPGDS) and neuropeptide S receptor 1 (NPSR1) were selected for further investigation. Significantly lower levels of both CCL5 and HPGDS were found in children with persistent asthma, while NPSR1 was found at higher levels in children with mild intermittent asthma compared to healthy controls. In addition, the protein levels were investigated in another respiratory disease, sarcoidosis, showing significantly higher NPSR1 levels in sera from sarcoidosis patients compared to healthy controls. Immunohistochemical staining of healthy tissues revealed high cytoplasmic expression of HPGDS in mast cells, present in stroma of both airway epithelia, lung as well as in other organs. High expression of NPSR1 was observed in neuroendocrine tissues, while no expression was observed in airway epithelia or lung. In conclusion, we have utilized a broad-scaled affinity proteomics approach to identify three proteins with altered plasma levels in asthmatic children, representing one of the first evaluations of HPGDS and NPSR1 protein levels in plasma.

MP-AzeFlu is more effective than fluticasone propionate for the treatment of allergic rhinitis in children.

The objective was to evaluate the efficacy of MP-AzeFlu (Dymista(®) ) vs fluticasone propionate (FP), (both 1 spray/nostril bid), in children with allergic rhinitis (AR). MP-AzeFlu combines azelastine hydrochloride, FP and a novel formulation in a single spray. Children were randomized in a 3 : 1 ratio to MP-AzeFlu or FP in this open-label, 3-month study. Efficacy was assessed in children aged ≥ 6 to <12 years (MP-AzeFlu: n = 264; FP: n = 89), using a 4-point symptom severity rating scale from 0 to 3 (0 = no symptoms; 3 = severe symptoms). Over the 3-month period, MP-AzeFlu-treated children experienced significantly greater symptom relief than FP-treated children (Diff: -0.14; 95% CI: -0.28, -0.01; P = 0.04), noted from the first day (particularly the first 7 days) and sustained for 90 days. More MP-AzeFlu children achieved symptom-free or mild symptom severity status, and did so up to 16 days faster than FP. MP-AzeFlu provides significantly greater, more rapid and clinically relevant symptom relief than FP in children with AR.

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Hospitalizations due to allergic reactions in Finnish and Swedish children during 1999-2011.

BACKGROUND: Several authors have reported on allergic reactions that resulted in presentation to the emergency department. However, studies of the secular trend of hospitalizations for paediatric allergic reactions, including anaphylaxis, are scarce. The aim of this study was to describe the secular trends of hospitalizations for allergic reactions, including anaphylaxis, among children aged 0-19 years in Finland and Sweden, and to establish the trend of prescribed epinephrine auto-injectors (EAI) among paediatric populations. METHODS: Using national databases, we identified hospitalizations between 1999 and 2011 with the primary diagnosis of allergic reaction per International Classification of Diseases, 10th Revision. RESULTS: Hospitalizations for allergic reactions totalled 1987 in Finland and 5433 in Sweden. Incidence rates increased in both countries. In Finland, the incidence of admission was 7.8 per 100 000 person-years at the start of the study period and 15.8 at the end of the study period. The corresponding numbers among Swedish children were 13.7 and 31.8 per 100 000 person-years. In Finland, 60% of children hospitalized were aged under 10 years. In Sweden, this proportion was somewhat lower, at 48%. Most hospitalizations occurred between May and September. The prevalence of EAI prescriptions in Finland increased by fourfold during the study period. In Sweden, such an increase was not identified. CONCLUSIONS: The incidence of allergic reactions leading to hospitalizations between 1999 and 2011 increased in Finland and Sweden among children aged 0 to 19 years. In Finland, the incidence was lower throughout the study period compared to Sweden. Younger children constituted the majority of hospitalized children.

Characterization of genetic variation in TLR8 in relation to allergic rhinitis.

BACKGROUND: A previous investigation of all 10 TLR genes for associations with allergic rhinitis (AR) detected a number of significant SNPs in the TLR8 locus. The associations indicated that an accumulation of rare variants could explain the signal. This study therefore searches for rare variants in the TLR8 region and also investigates the reproducibility of previous SNP associations. METHODS: The TLR8 gene was resequenced in 288 AR patients from Malmö and the data were compared with publically available data. Seven previously AR-associated SNPs from TLR8 were analyzed for AR associations in 422 AR patients and 859 controls from the BAMSE cohort. The associations detected in present and previous studies were compared. RESULTS: Sequencing detected 13 polymorphisms (three promotor and 10 coding) among 288 AR patients. Four of the coding polymorphisms were rare (MAF < 1%) and three of those were novel. Two coding polymorphisms were benign missense mutations and the rest were synonymous. Comparison with 1000Genomes and Exome Aggregation Consortium data revealed no accumulation of rare variants in the AR cases. The AR association tests made using the BAMSE cohort yielded five P-values <0.05. Tests of IgE levels yielded four significant SNP associations to birch pollen. Comparing results between different populations revealed opposing risk alleles, different gender effects, and response to different allergens in the different populations. CONCLUSIONS: Rare variants in TLR8 are not associated with AR. Comparison of present and previous association studies reveals contradictory results for common variants. Thus, no associations exist between genetic variation in TLR8 and AR.