Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data.

A popular hypothesis known as the atopic march proposes a set of sequential allergy and respiratory disorders in early childhood contributes enormously to the burden of disease in developed countries. Although the concept of the atopic march has been refined and strengthened by many cross-sectional and longitudinal studies linking eczema as the initial manifestation with progression to hay fever and then asthma, there is yet no definitive proof that the atopic march is the primary causal factor in childhood allergic disease. This debate is mainly related to the controversy around potential confounding of these associations by genetic and environmental factors. Family studies are ideally suited to unravelling the role of these factors. While multiple reviews have synthesized evidence from studies investigating this question, no review to date has explored specific evidence generated by twin and sibling studies to understand the aetiology of atopic march diseases. Our aim was to conduct a systematic review of twin and sibling studies that examine the allergic phenotypes that form the atopic march, to determine whether such analyses of data from these studies attempt to control for the effect confounding by shared factors, and to report estimates of the magnitude of associations between multiple phenotypes. Our review suggests that (1) genetics play a bigger role predisposing eczema to hay fever and eczema to asthma than environmental factors, and (2) the link between eczema and asthma and hay fever is independent of shared early-life environmental factors.

The effects of growing up on a farm on adult lung function and allergic phenotypes: an international population-based study.

RATIONALE: Evidence has suggested that exposure to environmental or microbial biodiversity in early life may impact subsequent lung function and allergic disease risk. OBJECTIVES: To investigate the influence of childhood living environment and biodiversity indicators on atopy, asthma and lung function in adulthood. METHODS AND MEASUREMENTS: The European Community Respiratory Health Survey II investigated ∼10 201 participants aged 26-54 years from 14 countries, including participants' place of upbringing (farm, rural environment or inner city) before age 5 years. A 'biodiversity score' was created based on childhood exposure to cats, dogs, day care, bedroom sharing and older siblings. Associations with lung function, bronchial hyper-responsiveness (BHR), allergic sensitisation, asthma and rhinitis were analysed. MAIN RESULTS: As compared with a city upbringing, those with early-life farm exposure had less atopic sensitisation (adjusted OR 0.46, 95% CI 0.37 to 0.58), atopic BHR (0.54 (0.35 to 0.83)), atopic asthma (0.47 (0.28 to 0.81)) and atopic rhinitis (0.43 (0.32 to 0.57)), but not non-atopic outcomes. Less pronounced protective effects were observed for rural environment exposures. Women with a farm upbringing had higher FEV1 (adjusted difference 110 mL (64 to 157)), independent of sensitisation and asthma. In an inner city environment, a higher biodiversity score was related to less allergic sensitisation. CONCLUSIONS: This is the first study to report beneficial effects of growing up on a farm on adult FEV1. Our study confirmed the beneficial effects of early farm life on sensitisation, asthma and rhinitis, and found a similar association for BHR. In persons with an urban upbringing, a higher biodiversity score predicted less allergic sensitisation, but to a lesser magnitude than a childhood farm environment.

Genetic variation at the Th2 immune gene IL13 is associated with IgE-mediated paediatric food allergy.

BACKGROUND: Food allergies pose a considerable world-wide public health burden with incidence as high as one in ten in 12-month-old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE class switching in B cells. OBJECTIVE: Here, we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. METHOD: We genotyped nine IL13 "tag" single nucleotide polymorphisms (tag SNPs) in 367 challenge-proven food allergic cases, 199 food-sensitized tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month-old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located sample of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication sample phenotypes were defined by clinical history of reactivity, 95% PPV or challenge, and IL13 genotyping was performed. RESULTS: IL13 rs1295686 was associated with challenge-proven food allergy in the discovery sample (P=.003; OR=1.75; CI=1.20-2.53). This association was also detected in the replication sample (P=.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis (P=.0006, OR=1.50). However, we cannot rule out an association with food sensitization. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. CONCLUSIONS AND CLINICAL RELAVANCE: We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy.

Genomewide association study of peanut allergy reproduces association with amino acid polymorphisms in HLA-DRB1.

BACKGROUND: Genetic variants for IgE-mediated peanut allergy are yet to be fully characterized and to date only one genomewide association study (GWAS) has been published. OBJECTIVE: To identify genetic variants associated with challenge-proven peanut allergy. METHODS: We carried out a GWAS comparing 73 infants with challenge-proven IgE-mediated peanut allergy against 148 non-allergic infants (all ~ 1 year old). We tested a total of 3.8 million single nucleotide polymorphisms, as well as imputed HLA alleles and amino acids. Replication was assessed by de novo genotyping in a panel of additional 117 cases and 380 controls, and in silico testing in two independent GWAS cohorts. RESULTS: We identified 21 independent associations at P ≤ 5 × 10-5 but were unable to replicate these. The most significant HLA association was the previously reported amino acid variant located at position 71, within the peptide-binding groove of HLA-DRB1 (P = 2 × 10-4 ). Our study therefore reproduced previous findings for the association between peanut allergy and HLA-DRB1 in this Australian population. CONCLUSIONS AND CLINICAL RELEVANCE: Genetic determinants for challenge-proven peanut allergy include alleles at the HLA-DRB1 locus.

The skin barrier function gene SPINK5 is associated with challenge-proven IgE-mediated food allergy in infants.

BACKGROUND: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. OBJECTIVE: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. METHOD: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. RESULTS: SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. CONCLUSIONS: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.

Nut allergy prevalence and differences between Asian-born children and Australian-born children of Asian descent: a state-wide survey of children at primary school entry in Victoria, Australia.

BACKGROUND: Asian infants born in Australia are three times more likely to develop nut allergy than non-Asian infants, and rates of challenge-proven food allergy in infants have been found to be unexpectedly high in metropolitan Melbourne. To further investigate the risk factors for nut allergy, we assessed the whole-of-state prevalence distribution of parent-reported nut allergy in 5-year-old children entering school. METHODS: Using the 2010 School Entrant Health Questionnaire administered to all 5-year-old children in Victoria, Australia, we assessed the prevalence of parent-reported nut allergy (tree nut and peanut) and whether this was altered by region of residence, socio-economic status, country of birth or history of migration. Prevalence was calculated as observed proportion with 95% confidence intervals (CI). Risk factors were evaluated using multivariable logistic regression and adjusted for appropriate confounders. RESULTS: Parent-reported nut allergy prevalence was 3.1% (95% CI 2.9-3.2) amongst a cohort of nearly 60 000 children. It was more common amongst children of mothers with higher education and socio-economic index and less prevalent amongst children in regional Victoria than in Melbourne. While children born in Australia to Asian-born mothers (aOR 2.67, 95% CI 2.28-3.27) were more likely to have nut allergy than non-Asian children, children born in Asia who subsequently migrated to Australia were at decreased risk of nut allergy (aOR 0.1, 95% CI 0.03-0.31). CONCLUSION: Migration from Asia after the early infant period appears protective for the development of nut allergy. Additionally, rural regions have lower rates of nut allergy than urban areas.

Relationships between adult asthma and oxidative stress markers and pH in exhaled breath condensate: a systematic review.

Oxidative stress has a recognized role in the pathophysiology of asthma. Recently, interest has increased in the assessment of pH and airway oxidative stress markers. Collection of exhaled breath condensate (EBC) and quantification of biomarkers in breath samples can potentially indicate lung disease activity and help in the study of airway inflammation, and asthma severity. Levels of oxidative stress markers in the EBC have been systematically evaluated in children with asthma; however, there is no such systematic review conducted for adult asthma. A systematic review of oxidative stress markers measured in EBC of adult asthma was conducted, and studies were identified by searching MEDLINE and SCOPUS databases. Sixteen papers met the inclusion criteria. Concentrations of exhaled hydrogen ions, nitric oxide products, hydrogen peroxide and 8-isoprostanes were generally elevated and related to lower lung function tests in adults with asthma compared to healthy subjects. Assessment of EBC markers may be a noninvasive approach to evaluate airway inflammation, exacerbations, and disease severity of asthma, and to monitor the effectiveness of anti-inflammatory treatment regimens. Longitudinal studies, using standardized analytical techniques for EBC collection, are required to establish reference values for the interpretation of EBC markers in the context of asthma.

Mould-sensitized adults have lower Th2 cytokines and a higher prevalence of asthma than those sensitized to other aeroallergens.

BACKGROUND: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. METHODS: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. RESULTS: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47-54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6-5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06-10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10-0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30-0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24-1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. CONCLUSION: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.

Identification of STOML2 as a putative novel asthma risk gene associated with IL6R.

BACKGROUND: Functional variants in the interleukin-6 receptor gene (IL6R) are associated with asthma risk. We hypothesized that genes co-expressed with IL6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes. METHODS: To identify genes whose expression was correlated with that of IL6R, we analyzed gene expression levels generated for 373 human lymphoblastoid cell lines by the Geuvadis consortium and for 38 hematopoietic cell types by the Differentiation Map Portal (DMAP) project. Genes correlated with IL6R were then screened for nearby single nucleotide polymorphisms (SNPs) that were significantly associated with both variation in gene expression levels (eSNPs) and asthma risk. RESULTS: We identified 90 genes with expression levels correlated with those of IL6R and that also had a nearby eSNP associated with disease risk in a published asthma GWAS (N = 20 776). For 16 (18%) genes, the association between the eSNP and asthma risk replicated with the same direction of effect in a further independent published asthma GWAS (N = 27 378). Among the top replicated associations (FDR < 0.05) were eSNPs for four known (IL18R1, IL18RAP, BCL6, and STAT6) and one putative novel asthma risk gene, stomatin-like protein 2 (STOML2). The expression of STOML2 was negatively correlated with IL6R, while eSNPs that increased the expression of STOML2 were associated with an increased asthma risk. CONCLUSION: The expression of STOML2, a gene that plays a key role in mitochondrial function and T-cell activation, is associated with both IL-6 signaling and asthma risk.

Exposure to 'farming' and objective markers of atopy: a systematic review and meta-analysis.

There is growing interest in the 'farm effect' on the spectrum of allergy. Evidence concerning the farm effect on asthma, eczema, and allergic rhinitis has been systematically synthesized, but without a specific focus on objective markers of sensitization. This focus is important, as farm exposures may be related to allergy but not to non-allergic phenotypes of disease. We aimed to systematically review and meta-analyse literature that has investigated associations between farm exposure at any age and objective measures of atopy, that is serum IgE or skin prick tests results. Using predefined inclusion and exclusion criteria, we identified 29 articles for review. IgE levels were measured in either childhood or adulthood by eighteen studies, while skin prick testing was performed in sixteen studies. Newcastle-Ottawa Scale quality assessments indicated that the majority of these studies demonstrated a representative sample of selected participants. Due to significant heterogeneity in study measures and methodology between studies, only few were meta-analysed. This meta-analysis showed a significant protective effect of farm exposure before 1 year of life on allergic sensitization (OR = 0.60 [0.52-0.70]). Farm exposure during childhood was also associated with a reduced risk of sensitization to cat or timothy (OR = 0.60 [0.51-0.70]; OR=0.46 [0.41-0.51]). Studies investigating the effect of farm exposure in adult life could not be meta-analysed, and their results were inconsistent. Insufficient studies investigated food sensitization as an outcome to allow synthesis. The majority of studies included in this review investigated childhood farm exposure, finding evidence to support a protective childhood 'farm effect' against subsequent atopy. There is inconsistent evidence on the association between farm exposure in adulthood and allergic sensitization. Further studies are needed to tease out the exact exposures and timing associated with farming environments that protect against allergic disease.

Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis.

BACKGROUND: Food allergy, eczema and wheeze are early manifestations of allergic disease and commonly co-occur in infancy although their interrelationship is not well understood. Data from population studies are essential to determine whether there are differential drivers of multi-allergy phenotypes. We aimed to define phenotypes and risk factors of allergic disease using latent class analysis (LCA). METHODS: The HealthNuts study is a prospective, population-based cohort of 5276 12-month-old infants in Melbourne, Australia. LCA was performed using the following baseline data collected at age 12 months: food sensitization (skin prick test ≥ 2 mm) and allergy (oral food challenge) to egg, peanut and sesame; early (< 4 months) and late-onset eczema; and wheeze in the first year of life. Risk factors were modelled using multinomial logistic regression. RESULTS: Five distinct phenotypes were identified: no allergic disease (70%), non-food-sensitized eczema (16%), single egg allergy (9%), multiple food allergies (predominantly peanut) (3%) and multiple food allergies (predominantly egg) (2%). Compared to the baseline group of no allergic disease, shared risk factors for all allergic phenotypes were parents born overseas (particularly Asia), delayed introduction of egg, male gender (except for single egg allergy) and family history of allergic disease, whilst exposure to pet dogs was protective for all phenotypes. Other factors including filaggrin mutations, vitamin D and the presence of older siblings differed by phenotype. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple outcomes in infancy can be used to determine five distinct allergy phenotypes at the population level, which have both shared and separate risk factors suggesting differential mechanisms of disease.

Atopic dermatitis and the atopic march revisited.

Atopic dermatitis (AD) has become a significant public health problem because of increasing prevalence, together with increasing evidence that it may progress to other allergic phenotypes. While it is now acknowledged that AD commonly precedes other allergic diseases, a link termed 'the atopic march', debate continues as to whether this represents a causal relationship. An alternative hypothesis is that this association may be related to confounding by familial factors or phenotypes that comanifest, such as early-life wheeze and sensitization. However, there is increasing evidence from longitudinal studies suggesting that the association between AD and other allergies is independent of confounding by comanifest allergic phenotypes. The hypotheses on plausible biological mechanisms for the atopic march focus on defective skin barrier function and overexpression of inflammatory mediators released by the skin affected by AD (including thymic stromal lymphopoietin). Both human and animal studies have provided evidence supporting these potential biological mechanisms. Evidence from prevention trials is now critical to establishing a causal nature of the atopic march. An emerging area of research is investigation into environmental modifiers of the atopic march. Such information will assist in identifying secondary prevention strategies to arrest the atopic march. Despite much research into the aetiology of allergies, little progress has been made in identifying effective strategies to reduce the burden of allergic conditions. In this context, the atopic march remains a promising area of investigation.

CD14 polymorphisms, microbial exposure and allergic diseases: a systematic review of gene-environment interactions.

Asthma and allergy may develop as a result of interactions between environmental factors and the genetic characteristics of an individual. This review aims to summarize the available evidence for, and potential effects of, an interaction between polymorphisms of the CD14 gene and exposure to microbes on the risk of asthma and allergic diseases. We searched PubMed, MEDLINE and Global Health databases, finding 12 articles which met inclusion criteria. Most studies reported a significant interaction between CD14 polymorphisms and microbial exposure. When stratified by age at microbial exposure (early life vs adult life), there was evidence of a protective effect of gene-environment interaction against atopy in children, but not adults. We also found different effects of interaction depending on the type of microbial exposures. There was no strong evidence for asthma and eczema. Future studies should consider a three-way interaction between CD14 gene polymorphisms, microbial exposures and the age of exposure.

Persistent pollen exposure during infancy is associated with increased risk of subsequent childhood asthma and hayfever.

BACKGROUND: Few studies have focused on pollen exposure and asthma in children. None have examined associations between persistent exposure to pollen in infancy and aeroallergen sensitisation and asthma in childhood. OBJECTIVES: To examine the association between higher ambient levels of pollen in the first 3-6 months of life and risk of eczema, sensitization to food and aeroallergens at 2 years and asthma or hayfever at age 6-7 years combined. METHODS: Using a birth cohort of 620 infants with a family history of allergic disease born between 1990 and 1994, we examined risk of eczema or allergic sensitization (SPT > 3 mm to at least one of cow's milk, egg white, peanut, house dust-mite, rye grass, and cat dander) by age 2 and asthma or hayfever at age 6-7. Daily ambient levels of pollen were measured during this period. RESULTS: Cumulative exposure to pollen concentrations up to 6 months was associated with aeroallergen sensitization with the highest risk occurring at 3 months (aOR = 1.34, 95% CI 1.06-1.72). Cumulative exposure to pollen up to 3 months was also associated with hayfever (aOR = 1.14, 95% CI 1.009-1.29) and between 4 and 6 months exposure with asthma only (aOR=1.35, 95% CI 1.07-1.72). CONCLUSION: Persistent pollen exposure in infancy appears to increase the risk of asthma and hayfever in children. These results support the hypothesis that there is a critical window of opportunity in early development which may be important for modification of allergic outcomes.

Adult serum cytokine concentrations and the persistence of asthma.

BACKGROUND: Cytokines play a pivotal role in regulating the development and persistence of the inflammatory process in asthma. Our aim was to investigate whether asthma persistence or remission is associated with a specific cytokine profile. METHODS: The Tasmanian Longitudinal Health Study followed participants from 7 to 44 years of age. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10 and tumor necrosis factor-alpha (TNF-α) were measured at age 44 years. Participants were categorized into five phenotypes (early-onset noncurrent asthma, early-onset current asthma, late-onset noncurrent asthma and late-onset current asthma). Those who had never had asthma formed the reference group. Multivariable linear regression was used to compare serum cytokine concentrations between each phenotype and the reference group. RESULTS: IL-10 concentrations were significantly lower in serum from the early-onset current asthma group than in the reference group (ratio of geometric means 0.58; 95% confidence interval 0.33-0.99; p = 0.048). IL-6 concentrations for the late-onset remitted group were also significantly lower than in the reference group (p = 0.009). The TNF-α concentrations were significantly lower for both early-and late-onset remitted asthma phenotypes when compared with the reference group. No associations were detected between serum concentrations of IL-4, IL-5 or IL-8 and these specific longitudinal asthma phenotypes. CONCLUSION: Our findings suggest a possible role for deficient IL-10 responses in the persistence of early-onset asthma. Lower IL-6 and TNF-α concentrations in serum from those with remitted asthma suggest that these proinflammatory cytokines may be actively suppressed during asthma remission.

Understanding the evidence for and against the role of breastfeeding in allergy prevention.

The relationship between breastfeeding and allergic disease risk has been controversial. This article reviews the current evidence for the role of breastfeeding in the prevention of allergic disease. We found considerable methodological limitations inherent in most studies evaluating the effect of breastfeeding in allergic disease. Nevertheless, since randomized control trials in breast feeding research would be considered unethical, the evidence remains limited to poorer quality observational studies where participation and recall bias can severely affect the objectivity of the data collected. Furthermore, reporting of type of breastfeeding (exclusive, full or partial) may be biased by a participant's inherent belief system of what they think they should be doing. Current evidence is inconclusive regarding the effect of breastfeeding on the development of eczema, with the most recent systemic review reporting no protective effect. There is insufficient data regarding the effects of breastfeeding on objective measures of food allergy at any age. Studies show a paradoxical effect of breastfeeding on the prevention of asthma, with an apparent protective effect against early wheezing illness in the first years of life yet an increased risk of asthma in later life; however, these findings must be interpreted with caution. Existing studies fail to adequately adjust for confounders, including the critical issues of protection against early life respiratory illnesses and reverse causation. Therefore, it is possible that the effect of breastfeeding on early wheezing illness reflects protection against respiratory infection, the predominant trigger of wheezing in early childhood, rather than a true reduction in risk of asthma. In summary, future research that takes into account the potential contribution of confounding factors and effect modifiers is needed to clarify the role of breastfeeding in development of allergic disease and to inform current clinical guidelines on the prevention of allergic disease.

Pets at birth do not increase allergic disease in at-risk children.

BACKGROUND: The literature is contradictory concerning pet exposure and risk of allergic disease in childhood especially among those with a family history of allergy. OBJECTIVE: To investigate the relationship between cat and dog exposure at birth and allergic outcomes over the first 12 years in a birth cohort selected for familial allergy. METHODS: A prospective birth cohort of 620 infants with a family history of allergic diseases was recruited. Data on pet keeping, family demographics and cord blood samples were collected at birth. Information on childhood wheeze, eczema and hay fever was collected 18 times in the first 2 years, at 7 years and at 12 years. Skin prick tests were conducted at 2, 7 and 12 years, and in parents. Regression analyses were used to investigate the relevant associations while adjusting for potential confounders. RESULTS: Exposure to cats or dogs at birth showed a moderate reduction in risk of wheeze (aOR = 0.76; 95% CI 0.53, 1.09) and hay fever (aOR = 0.71; 0.49, 1.02) after 7 years of age. Protective effects were stronger in children of non-sensitized fathers (aOR wheeze 0.55; 0.31, 0.98; aOR hay fever 0.33; 0.15, 0.77 on exposure to cats alone, or cats or dogs at birth). Pet keeping was not related to cord blood IgE or sensitization from 2 to 12 years. CONCLUSIONS AND CLINICAL RELEVANCE: Pets at birth either decreased or had no effect on allergic disease up to age 12. We found no evidence that exposure to cats or dogs at birth increases the risk of allergic disease in high-risk children.

Positionally cloned genes and age-specific effects in asthma and atopy: an international population-based cohort study (ECRHS).

BACKGROUND: Several genes identified by positional cloning have been associated with asthma and atopy, but few findings have been replicated. Age at onset of asthma has been associated with different phenotypic characteristics, and with variants at chromosome 17q21 identified through genome-wide association. This study examined the associations and age-specific effects on asthma, atopy and bronchial hyper-responsiveness (BHR) of five candidate genes previously identified by positional cloning (ADAM33, PHF11, NPSR1, DPP10, SPINK5). METHODS: 51 polymorphisms from 2474 participants from 13 countries who took part in the European Community Respiratory Health Survey (1990-2000) were studied. Asthma and age at onset of asthma were assessed by questionnaire data, BHR by methacholine challenge and atopy by specific immunoglobulin E to four common allergens. RESULTS: Significant associations with asthma, atopy and particularly for asthma with atopy were observed for a large region of 47 kb in the NPSR1 gene, even after Bonferroni correction for multiple comparisons (p<0.001). The associations with NPSR1 were stronger in those reporting a first attack of asthma before the age of 15, with statistically significant interactions with age of onset found for three SNPs. The evidence for ADAM33 and BHR and for an age-specific effect of two SNPs in DPP10 and asthma was weaker. CONCLUSION: This study provides further evidence for an effect of NPSR1 on asthma, atopy and atopic asthma. In addition, this analysis suggests a role for NPSR1 in early-onset asthma driven by the strong effect of this gene on atopic asthma.