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.

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Breastfeeding and cardiometabolic markers at age 12: a population-based birth cohort study.

BACKGROUND: There is growing evidence for a protective effect of breastfeeding against overweight and diabetes. It is less clear though, whether breastfed infants also have a more favorable cardiometabolic profile in childhood. OBJECTIVE: We investigated whether children who were breastfed in infancy had more favorable cardiometabolic markers at 12 years of age than children who were never breastfed and received formula milk instead, and whether associations depended on the duration of breastfeeding. METHODS: In 1509 participants of the population-based PIAMA birth cohort study, cardiometabolic markers were measured at 12 years of age. Duration of breastfeeding in weeks was assessed through parental questionnaires at 3 months and 1 year of age. Multivariable linear regression analysis was used to investigate associations of breastfeeding (any vs. never breastfeeding and duration of breastfeeding in categories <3 months, 3 to <6 months, and ≥6 months breastfeeding vs. never breastfeeding) with systolic and diastolic blood pressure (SBP and DBP, in Z-scores adjusted for age, sex, and height), total-to-high-density lipoprotein cholesterol (TC/HDLC), glycated hemoglobin (HbA1c, in mmol/mol), body mass index (BMI, in Z-scores adjusted for age and sex) and waist circumference (WC, in cm). Multivariable logistic regression was used to investigate the association of breastfeeding with odds of being overweight. RESULTS: 1288 of 1509 children (85.3%) received any breastmilk in infancy. Breastfed children had a lower SBP Z-score (-0.21 SD (≈ -2.29 mmHg), 95% CI -0.37, -0.06), a lower DBP Z-score (-0.10 SD (≈ -1.19 mmHg), 95% CI -0.20, -0.00), a smaller WC (-1.12 cm, 95% CI -2.20; -0.04), and lower odds of being overweight (OR 0.61, 95% CI 0.38, 0.97) than never breastfed children. These associations were not different between children with shorter and longer duration of breastfeeding. No statistically significant differences in TC/HDLC, HbA1c, and BMI were observed between breastfed and never breastfed children. CONCLUSIONS: We observed that breastfeeding was associated with a lower blood pressure, a smaller waist circumference and a lower risk of overweight in 12-year old children. These associations were independent of the duration of breastfeeding. No associations were observed between breastfeeding and other cardiometabolic markers.

Asthma in 9-year-old children of subfertile couples is not associated with in vitro fertilization procedures.

Asthma is a chronic reversible obstructive airway disease, which is common among children and leads to respiratory impairment. Studies showed that asthma is more common among children born after in vitro fertilization (IVF) than among spontaneously conceived children. However, it is unknown which component of the IVF procedure contributes to this putative link. Therefore, the aim of this prospective follow-up study was to differentiate the possible effect of ovarian hyperstimulation from that of the in vitro culture procedure on asthma and rhinitis in 9-year-old children conceived with IVF. The study comprised three groups of singletons: (I) conceived with ovarian hyperstimulation-IVF (COH-IVF, n = 95); (II) conceived with modified natural cycle-IVF (MNC-IVF, n = 48); and (III) naturally conceived to subfertile couples (Sub-NC, n = 68). Parents filled out the validated Dutch version of the asthma questionnaire of the International Study of Asthma and Allergies. Asthma prevalence in the groups did not differ: COH-IVF n = 8 (8%); MNC-IVF n = 0 (0%); and Sub-NC n = 4 (6%). Adjustment for confounders did not alter the results.Conclusion: Neither ovarian hyperstimulation nor the in vitro culture procedure was associated with asthma and rhinitis at 9 years. IVF children had a similar prevalence of asthma compared with children conceived naturally by subfertile couples.Trial registration: ISRCTN76355836 What is Known: • An increased risk for asthma has been observed in children born after in vitro fertilization at preschool and school age. • The association between IVF and asthma may be partly explained by parental subfertility. What is New: • IVF children do not have a higher prevalence of asthma than children of subfertile couples conceived naturally. • Ovarian hyperstimulation used in IVF is not associated with asthma in 9-year-old children of subfertile couples.

Novel genes and insights in complete asthma remission: A genome-wide association study on clinical and complete asthma remission.

BACKGROUND: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. OBJECTIVE: We performed a GWA study to develop insights in asthma remission. METHODS: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. RESULTS: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. CONCLUSIONS AND CLINICAL RELEVANCE: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.

Association of STAT6 gene variants with food allergy diagnosed by double-blind placebo-controlled food challenges.

This study describes the role of two STAT6 gene variants in food allergy using data of patients and their parents who underwent double-blind placebo-controlled food challenges (DBPCFCs). After quality control, 369 trios were analysed including 262 children (71.0%) with food allergy. Associations were tested by the Family based association test. The A alleles of both SNPs were associated with food allergy (P = .036 and P = .013 for rs324015 and rs1059513, respectively). Furthermore, these A alleles were associated with peanut allergy, higher sIgE levels to both peanut and cow's milk, more severe symptoms and higher eliciting doses during peanut and cow's milk DBPCFCs (all P < .05). In silico analysis indicates that the identified risk variants increase STAT6 expression which stimulates the differentiation of CD4 +  T cells to the Th2 subset. In conclusion, STAT6 variants may be involved in the pathophysiology of food allergy and their role seems to be independent of the allergenic food.

Prediction of the severity of allergic reactions to foods.

BACKGROUND: There is currently considerable uncertainty regarding what the predictors of the severity of diagnostic or accidental food allergic reactions are, and to what extent the severity of such reactions can be predicted. OBJECTIVE: To identify predictors for the severity of diagnostic and accidental food allergic reactions and to quantify their impact. METHODS: The study population consisted of children with a double-blind, placebo-controlled food challenge (DBPCFC)-confirmed food allergy to milk, egg, peanut, cashew nut, and/or hazelnut. The data were analyzed using multiple linear regression analysis. Missing values were imputed using multiple imputation techniques. Two scoring systems were used to determine the severity of the reactions. RESULTS: A total of 734 children were included. Independent predictors for the severity of the DBPCFC reaction were age (B = 0.04, P = .001), skin prick test ratio (B = 0.30, P < .001), eliciting dose (B = -0.09, P < .001), level of specific immunoglobulin E (B = 0.15, P < .001), reaction time during the DBPCFC (B = -0.01, P = .004), and severity of accidental reaction (B = 0.08, P = .015). The total explained variance of this model was 23.5%, and the eliciting dose only contributed 4.4% to the model. Independent predictors for more severe accidental reactions with an explained variance of 7.3% were age (B = 0.03, P = .014), milk as causative food (B = 0.77, P < .001), cashew as causative food (B = 0.54, P < .001), history of atopic dermatitis (B = -0.47, P = .006), and severity of DBPCFC reaction (B = 0.12, P = .003). CONCLUSIONS: The severity of DBPCFCs and accidental reactions to food remains largely unpredictable. Clinicians should not use the eliciting dose obtained from a graded food challenge for the purposes of making risk-related management decisions.

Childhood infections and common carotid intima media thickness in adolescence.

Atherosclerotic changes can be measured as changes in common carotid intima media thickness (CIMT). It is hypothesised that repeated infection-associated inflammatory responses in childhood contribute to the atherosclerotic process. We set out to determine whether the frequency of infectious diseases in childhood is associated with CIMT in adolescence. The study is part of the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) population-based birth cohort. At age 16 years, common CIMT was measured. We collected general practitioner (GP) diagnosed infections and prescribed antibiotics. Parent-reported infections were retrieved from annual questionnaires. Linear regression analysis assessed the association between number of infections during the first 4 years of life and common CIMT. Common CIMT measurement, GP and questionnaire data were available for 221 participants. No association was observed between the infection measures and CIMT. In a subgroup analysis, significant positive associations with CIMT were observed in participants with low parental education for 2-3 or ⩾7 GP diagnosed infections (+26.4 µm, 95% CI 0.4-52.4 and +26.8 µm, 95% CI 3.6-49.9, respectively) and ⩾3 antibiotic prescriptions (+35.5 µm, 95%CI 15.8-55.3). Overall, early childhood infections were not associated with common CIMT in adolescence. However, a higher number of childhood infections might contribute to the inflammatory process of atherosclerosis in subgroups with low education, this needs to be confirmed in future studies.

Increased risk of asthma in overweight children born large for gestational age.

BACKGROUND: Being born large for gestational age (LGA) is a marker of increased growth velocity in fetal life and a risk factor for childhood overweight. Both being born LGA and childhood overweight may influence the development of asthma, although the role of overweight in the association between LGA and childhood asthma is unclear. Importantly, recent studies have suggested that the association between overweight and asthma may be related to non-allergic pathways. If this also applies to the association between LGA and asthma, the association between being born LGA and asthma may be different for atopic and non-atopic children. OBJECTIVE: We investigated the association of being LGA with the prevalence of asthma at age 8 in atopic and non-atopic children and the role of overweight in this association. METHODS: Complete data on asthma, anthropometry and atopy at age of 8 years, and potential confounders were available for 1608 participants of the PIAMA birth cohort. Odds ratios for the association between LGA and asthma in atopic and non-atopic children were estimated by logistic regression analysis adjusting for potential confounders. Overweight was assessed as a potential modifier of the association between LGA and asthma. RESULTS: Being born LGA was not significantly associated with asthma at age of 8 in atopic and non-atopic children. However, overweight at age of 8 years modified the association between asthma at age of 8 and LGA. In non-atopic children, children who were born LGA and were overweight at age of 8 years had a significantly increased odds of asthma compared to non-LGA, non-overweight children (adj OR 7.04; 95% CI 2.2-24). CONCLUSIONS: We observed that non-atopic children born LGA, who were overweight by 8 years have an increased risk of asthma. If confirmed, these findings suggest that non-atopic children born LGA may be identified early in life as a high-risk group for asthma.

Predictive value of serum sST2 in preschool wheezers for development of asthma with high FeNO.

Wheezing is common in childhood. However, current prediction models of pediatric asthma have only modest accuracy. Novel biomarkers and definition of subphenotypes may improve asthma prediction. Interleukin-1-receptor-like-1 (IL1RL1 or ST2) is a well-replicated asthma gene and associates with eosinophilia. We investigated whether serum sST2 predicts asthma and asthma with elevated exhaled NO (FeNO), compared to the commonly used Asthma Prediction Index (API). Using logistic regression modeling, we found that serum sST2 levels in 2-3 years-old wheezers do not predict doctors' diagnosed asthma at age 6 years. Instead, sST2 predicts a subphenotype of asthma characterized by increased levels of FeNO, a marker for eosinophilic airway inflammation. Herein, sST2 improved the predictive value of the API (AUC=0.70, 95% CI 0.56-0.84), but had also significant predictive value on its own (AUC=0.65, 95% CI 0.52-0.79). Our study indicates that sST2 in preschool wheezers has predictive value for the development of eosinophilic airway inflammation in asthmatic children at school age.

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma.

BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with P-values < 1*10-5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS: PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2.

Overweight patterns throughout childhood and cardiometabolic markers in early adolescence.

BACKGROUND: Risk of cardiovascular and metabolic disease is higher in adults who were relatively thin at birth and had subsequent accelerated weight gain. This specific pattern of weight gain may relate to unfavorable cardiometabolic markers already in childhood. We prospectively assessed whether children with different patterns of overweight development from age 3 months to 11 years had distinct levels of cardiometabolic markers at age 12 years. SUBJECTS/METHODS: We used data of 1500 children participating in the PIAMA birth cohort that started in 1996/1997. Parents reported height and weight during 10 waves of follow-up from age 3 months to 11 years. Four distinct overweight development patterns were derived using longitudinal latent class analysis; 'never'; 'early transient'; 'gradually developing' and 'persistent' overweight. Cardiometabolic markers (total-to-high-density lipoprotein cholesterol (TC/HDLC) ratio, blood pressure (BP), glycated hemoglobin (HbA1c)) were assessed at age 12 years in 1500 children. RESULTS: Children who developed overweight gradually and children with persistent overweight throughout childhood, at age 12 years had a 2-3-fold higher risk of having high (>90th centile) TC/HDLC ratio, systolic and diastolic BP, compared with children who were never overweight. In children who gradually developed overweight, TC/HDLC ratio was 0.75 higher (95% confidence interval (CI) 0.54-0.96); systolic BP 4.90 mmHg higher (95% CI 2.45-7.36) and diastolic BP 1.78 mmHg higher (95% CI 0.07-3.49) than in children who never had overweight. Estimates for children with persistent overweight were similar. CONCLUSIONS: Children with gradually developing overweight, and those with persistent overweight had unfavorable cholesterol and blood pressure levels already at age 12 years, whereas children with early transient overweight avoided these unfavorable outcomes. Our results support the hypothesis that specific overweight patterns predispose to an adverse cardiometabolic profile, which is already apparent in early adolescence before progressing to adult cardiometabolic disease.

Genetic variation in uncontrolled childhood asthma despite ICS treatment.

Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10(-5)), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.

The challenge of measuring IL-33 in serum using commercial ELISA: lessons from asthma.

BACKGROUND: Interleukin-33 (IL-33) has been subject of extensive study in the context of inflammatory disorders, particularly in asthma. Many human biological samples, including serum, have been used to determine the protein levels of IL-33, aiming to investigate its involvement in asthma. Reliable methods are required to study the association of IL-33 with disease, especially considering the complex nature of serum samples. OBJECTIVE: We evaluated four IL-33 ELISA kits, aiming to determine a robust and reproducible approach to quantifying IL-33 in human serum from asthma patients. METHODS: IL-33 levels were investigated in serum of well-defined asthma patients by the Quantikine, DuoSet (both R&D systems), ADI-900-201 (Enzo Life Sciences), and SKR038 (GenWay Biotech Inc San Diego USA) immunoassays, as well as spiking experiments were performed using recombinant IL-33 and its soluble receptor IL-1RL1-a. RESULTS: We show that 1) IL-33 is difficult to detect by ELISA in human serum, due to lack of sensitivity and specificity of currently available assays; 2) human serum interferes with IL-33 quantification, in part through IL-1RL1-a; and 3) using non-serum certified kits may lead to spurious findings. CONCLUSION AND CLINICAL RELEVANCE: If IL-33 is to be studied in the serum of asthma patients and other diseases, a more sensitive and specific assay method is required, which will be vital for further understanding and targeting of the IL-33/IL-1RL1 axis in human disease.

Association of season of birth with DNA methylation and allergic disease.

BACKGROUND: Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long-lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy. METHODS: In a subset of 18-year-old participants from the Isle of Wight (IoW) birth cohort (n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome-wide DNA methylation was measured, and season-associated CpGs detected using a training-and-testing-based technique. Validation method examined the 8-year-old Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third-generation cohort newborns. RESULTS: Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome-wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season-associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season-associated methylation was largely absent in newborns, suggesting it arises post-natally. CONCLUSIONS: This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved.

Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma.

BACKGROUND: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. METHODS: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. RESULTS: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature. CONCLUSIONS: Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.

Residential greenness is differentially associated with childhood allergic rhinitis and aeroallergen sensitization in seven birth cohorts.

BACKGROUND: The prevalence of allergic rhinitis is high, but the role of environmental factors remains unclear. We examined cohort-specific and combined associations of residential greenness with allergic rhinitis and aeroallergen sensitization based on individual data from Swedish (BAMSE), Australian (MACS), Dutch (PIAMA), Canadian (CAPPS and SAGE), and German (GINIplus and LISAplus) birth cohorts (n = 13 016). METHODS: Allergic rhinitis (doctor diagnosis/symptoms) and aeroallergen sensitization were assessed in children aged 6-8 years in six cohorts and 10-12 years in five cohorts. Residential greenness was defined as the mean Normalized Difference Vegetation Index (NDVI) in a 500-m buffer around the home address at the time of health assessment. Cohort-specific associations per 0.2 unit increase in NDVI were assessed using logistic regression models and combined in a random-effects meta-analysis. RESULTS: Greenness in a 500-m buffer was positively associated with allergic rhinitis at 6-8 years in BAMSE (odds ratio = 1.42, 95% confidence interval [1.13, 1.79]) and GINI/LISA South (1.69 [1.19, 2.41]) but inversely associated in GINI/LISA North (0.61 [0.36, 1.01]) and PIAMA (0.67 [0.47, 0.95]). Effect estimates in CAPPS and SAGE were also conflicting but not significant (0.63 [0.32, 1.24] and 1.31 [0.81, 2.12], respectively). All meta-analyses were nonsignificant. Results were similar for aeroallergen sensitization at 6-8 years and both outcomes at 10-12 years. Stratification by NO2 concentrations, population density, an urban vs rural marker, and moving did not reveal consistent trends within subgroups. CONCLUSION: Although residential greenness appears to be associated with childhood allergic rhinitis and aeroallergen sensitization, the effect direction varies by location.

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.