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Angela Simpson

Publications and source records attributed to Angela Simpson.

At least 19 recordsLinked to original sources
PubMed2025

Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modelling in vitro.

BACKGROUND: Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. RESULTS: The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. CONCLUSIONS: Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.

Atopic eczema↗
PubMed2006

What are we learning from genetic cohort studies?

Although genetic component of asthma has been well recognised, genetics alone cannot explain the rise in asthma prevalence. This increase is likely a consequence of environmental factors increasing the risk in genetically susceptible individuals. As wheezing illness usually begins within months of birth, prospective birth cohorts with detailed measures of environmental exposures and objective measures of disease are essential to study gene-environment interactions in the development of different wheeze phenotypes. Such studies will enable identification of children at increased risk of disease because of a genetic predisposition when exposed to a particular environmental factor. Tailor-made evidence-based strategies for prevention of asthma and atopic sensitization applicable to individuals at risk (rather than the whole population) will then be developed to reduce the risk of asthma and allergy development.

Asthma↗
PubMed2006

Exhaled breath condensate pH and childhood asthma: unselected birth cohort study.

RATIONALE: Exhaled breath condensate pH (EBC-pH) may be useful noninvasive marker for evaluation of patients with asthma. OBJECTIVES: To investigate the relationship between EBC-pH and symptoms suggestive of childhood asthma in an epidemiologic setting and examine its relation to lung function, airway hyperresponsiveness (AHR), and airway inflammation. METHODS: Within the context of a prospective population-based birth cohort, EBC was collected from 630 children at age 8 yr using the RTube (pH measured after deaeration with argon). Lung function was measured by spirometry (FEV1; n = 521) and plethysmography (sRaw; n = 567), and AHR by methacholine challenge (n = 498). Airway inflammation was assessed using exhaled nitric oxide (eNO; n = 305). RESULTS: EBC-pH values ranged widely (4.40-8.29), and did not differ between 54 children with parentally reported asthma and 562 nonasthmatic subjects (median [interquartile range]: 7.75 [7.45-7.85] vs. 7.77 [7.59-7.87]; p = 0.35). There was a trend for lower EBC-pH among current wheezers (n = 98; 7.72 [7.50-7.83]) compared with nonwheezers (n = 532; 7.77 [7.60-7.87]; p = 0.07). Wheeze frequency, severity, and use of antiasthma medication were not associated with EBC-pH. There was no consistent association between EBC-pH and lung function, airway reactivity, and airway inflammation (FEV1, sRaw, PD20 methacholine, or eNO). There was no significant difference in EBC-pH between current wheezers receiving asthma medication who had positive methacholine challenge compared with children without any of these features. CONCLUSIONS: In the epidemiologic setting, EBC-pH does not differ between children with and without parentally reported symptoms suggestive of asthma. We found no consistent association between EBC-pH and lung function, AHR, and airway inflammation in this sample from the general population.

Asthma↗
PubMed2006

Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment.

RATIONALE: High endotoxin exposure may reduce the risk of allergic sensitization. OBJECTIVE: To determine the relationship between a promoter polymorphism in the CD14 gene (CD14/-159 C to T) and endotoxin exposure in relation to the development of allergic sensitization, eczema, and wheeze within the setting of a birth cohort. METHODS: We genotyped 442 children (CD14/-159 C to T; rs2569190). We assessed children for allergic sensitization (IgE > 0.2 kU/L to at least one of seven allergens), eczema (physical examination), and parentally reported wheeze. Endotoxin was measured in house dust. MAIN RESULTS: Genotype frequencies were consistent with other populations (TT, 25%; CT, 47%; CC, 28%). Sensitization (present in 33% of children) was not associated with genotype. For children with TT and CT genotypes, there was no association between endotoxin and sensitization (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.71-1.23; p = 0.7; and OR, 0.90; 95% CI, 0.77-1.04; p = 0.16, respectively) or endotoxin and eczema (OR, 0.99; 95% CI, 0.81-1.20; p = 0.89; and OR, 1.38; 95% CI, 0.83-2.30; p = 0.22, respectively). In children with the genotype CC, increasing endotoxin load was associated with a marked and significant reduction in the risk of sensitization (OR, 0.70; 95% CI, 0.55-0.89; p = 0.004) and eczema (OR, 0.73; 95% CI, 0.56-0.95; p = 0.02). However, we observed an increased risk of nonatopic wheeze with increasing endotoxin exposure in children with the CC genotype (OR, 1.42; 95% CI, 1.01-1.99; p = 0.04) but not other genotypes. No effect was seen for atopic wheeze. CONCLUSIONS: Increasing endotoxin exposure is associated with reduced risk of allergic sensitization and eczema but with increased risk of nonatopic wheeze in children with the CC genotype at -159 of the CD14 gene. The impact of environmental endotoxin may be enhanced in individuals with this genotype.

Asthma↗
PubMed2006

Allergen avoidance in the secondary and tertiary prevention of allergic diseases: does it work?

Although allergen avoidance is widely recommended as part of a secondary and tertiary prevention strategy for allergic diseases, a clear-cut demonstration of its effectiveness is still lacking. Ongoing observational secondary prevention cohorts show that sensitisation to mite can be prevented in the short term by allergen avoidance measures, but further follow-up of these children is needed to show if this effect can be sustained, as well as to ascertain its impact on allergic disease. More well-designed trials are still required before we can give any conclusive advice to our patients. Considering the management of allergy, current evidence suggests that interventions in children (either single or multifaceted) may be associated with some beneficial effect on asthma control, but no conclusive evidence exists regarding rhinitis or eczema. Conversely, there is little evidence to support the recommendation of allergen avoidance methods in adults with asthma and rhinitis. There is a need for an adequately designed trial assessing the effects of a multifaceted intervention in this age group.

Allergens↗
PubMed2006

Domestic allergen and endotoxin exposure and allergic sensitization in Cyprus.

We investigated the relationship between domestic allergen and endotoxin exposure and allergic sensitization among children in Cyprus. We skin prick tested 128 children aged 15-16 yr (random samples of 85 children with self-reported asthma and 43 healthy controls) and measured their domestic exposure to endotoxin and allergens (mite, cat, and dog). We analyzed the data using multivariate logistic regression (adjusting for gender, area of residence and parental history) and presented the outcomes as odds ratios (OR) and 95% confidence intervals (CI). Among this selected population, 19% of children were sensitized to mite, 15% to cat and 7% to dog. Male gender (OR 2.74, 95% CI 1.18-6.38, p = 0.02), maternal history of allergic disease (OR 3.53, 95% CI 1.13-11.00, p = 0.03), increasing endotoxin (OR 1.58, 95% CI 1.00-2.49, p = 0.05) and residence in the district of Nicosia (OR 2.48, 95% CI 1.01-6.08, p = 0.05) were independent associates of allergic sensitization. Factors associated with mite sensitization were increasing Der p 1 and endotoxin exposure (OR 1.28, 95% CI 1.01-1.62, p = 0.04 and OR 1.76, 95% CI 1.01-3.08, p = 0.05, respectively) and living in an urban area (OR 6.80, 95% CI 1.37-33.67, p = 0.02). Sensitization to domestic pets was associated only with paternal allergic disease (cat: OR 5.68, 95% CI 1.57-23.56, p = 0.02; dog: OR 13.5, 95% CI 1.79-101.73, p = 0.01), but not with pet ownership or specific allergen or endotoxin exposure. In conclusion, mite allergen exposure was associated with sensitization to mite, but there was no association between cat and dog allergen exposure and specific sensitizations. Surprisingly, in this area, increasing endotoxin exposure was associated with an increased risk of sensitization.

Adolescent↗
PubMed2006

Atopic wheezing and early life antibiotic exposure: a nested case-control study.

Several factors including early-life antibiotic usage have been implicated in the rising prevalence of allergic sensitization and asthma. A nested case-control study comparing antibiotic exposure of 37 sensitized children with recurrent wheeze (age 3-5 yr) and 37 non-sensitized children who had never wheezed was carried out within a population-based birth cohort (matching for age, sex, parental atopy, allergen exposure, and pet ownership). We collected data on antibiotic prescriptions during first 3 yr of life (timing, type, indication) from the primary care medical records. Significantly, more cases than controls received one or more antibiotic courses during the first year of life (92% vs. 70%, p = 0.04). The median time to first antibiotic course was shorter for the cases than the controls (6 vs. 8 months, p = 0.03). The total number of antibiotic receipts was greater amongst cases in each of the first 3 yr of life, but this reached significance only when the whole three-year period was considered (249 vs. 182 courses, p = 0.05). The increased ratio of antibiotic receipt in cases over controls was highest in the first year of life (1.32, 95% CI 0.99-1.78). Significantly more cases than controls were prescribed antibiotics for lower respiratory tract infection during the first 3 yr (p = 0.007), but not during the first year of life (p = 0.52). Antibiotics use by class was similar in the two groups. Our data support the hypothesis that early life exposure to broad-spectrum antibiotics may have a causative role in sensitisation and the expression of wheeze.

Anti-Bacterial Agents↗
PubMed2005

IgE antibody quantification and the probability of wheeze in preschool children.

BACKGROUND: IgE-mediated sensitization is usually considered a dichotomous variable (either sensitized or not). Quantitative IgE antibody analysis may better predict the expression of wheeze. OBJECTIVE: Within the context of a population-based birth cohort, we investigated the association among wheeze, lung function, and specific IgE antibody levels. METHODS: Children (n = 521) were followed to age 5 years with repeated questionnaires, skin testing, and measurement of lung function (specific airway resistance) and specific serum IgE (ImmunoCAP). RESULTS: Using specific IgE as a continuous variable, the risk of current wheeze increased significantly with increasing IgE to mite, cat, and dog (P < .0001). When IgE levels to these 3 allergens were summed, the probability of current wheeze increased 1.33-fold (95% CI, 1.21-1.47; P < .0001) per logarithmic unit increase, corresponding to an odds ratio of 3.1 at 10 and 4.25 at 30 kU(A)/L (kilo units of Allergen per liter). Similarly, increasing sum of mite-specific, cat-specific, and dog-specific IgE was associated with reduced lung function (P = .004). Among sensitized children (n = 184), the sum of mite, cat, and dog IgE was the strongest associate of current wheeze (odds ratio, 1.28; 95% CI, 1.13-1.46; P < .001), corresponding to an odds ratio of 2.56 at 10 and 3.32 at 30 kU(A)/L. There was no association between current wheeze and the size of skin test wheal. Furthermore, the sum of IgE to mite, cat, and dog at age 3 years increased the risk of persistent wheeze by age 5 years (2.15-fold/logarithmic unit increase in the specific IgE). CONCLUSION: IgE-mediated sensitization is not an all or nothing phenomenon. The probability of wheeze and reduced lung function increases with increasing specific IgE antibody levels.

Airway Resistance↗
PubMed2005

Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function.

RATIONALE: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. OBJECTIVES: Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function. METHODS: Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus. MAIN RESULTS: Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV(1) (F+1, M+1, T1, and T2; p < or = 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18-4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. CONCLUSIONS: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.

ADAM Proteins↗
PubMed2005

Pets and the development of allergic sensitization.

Sensitization to pets remains a risk factor for asthma and rhinitis, and can occur in people who have never lived with a pet. Several reports have indicated that living with a pet reduces the risk for becoming sensitized to that pet. Having a pet in the home gives exposure to more than just allergens. In areas with high frequency of pet ownership, community exposure to pet allergens is almost certainly sufficient to induce sensitization among non-pet owners. In this review, we examine the results of recent studies that have investigated the relationship between pet ownership, specific sensitization to that pet, and allergic sensitization in general. For cat ownership, the results are inconsistent between studies of similar design, with some studies suggesting an increase in risk and others a decrease among cat owners. For dogs, results are more consistent, generally suggesting that owning a dog has no effect or indeed may be protective against the development of specific sensitization to dog and allergic sensitization in general.

Adolescent↗
PubMed2005

The role of allergen avoidance in the secondary prevention of atopic disorders.

PURPOSE OF REVIEW: Allergen avoidance is recommended as part of the treatment programme of many patients with allergic diseases in Europe and the USA. However, clinical trials of allergen avoidance tend to be small and the findings inconsistent. Several larger studies have recently been published, making a review of the new literature timely. RECENT FINDINGS: There have been two large double-blind, placebo-controlled studies on the use of encasings (mattress, pillow and duvet) as a single intervention in adults with asthma. In both studies, participants in the active and the control group showed an improvement in peak flow, but there was no difference between groups over a 12-month period. A further smaller study of encasings reported an improvement in peak flow from 1 week in the active group; this study, however, was only of 9 weeks' duration. In children, the use of encasings was associated with a reduction in asthma medication usage, but not until 6 months into the study. A multifaceted intervention study, with the intervention tailored to the child's sensitization status and home environment (including environmental tobacco smoke), resulted in significant reductions in emergency room visits and symptoms in the active group. SUMMARY: The evidence suggests that interventions in children (either single or multifaceted) are associated with a meaningful and sustained improvement in asthma control. However, for adults, allergen proof encasings as a single intervention cannot be recommended. There is a need for a large-scale multifaceted intervention study in adults with asthma.

Adult↗
PubMed2004

Behavior problems antecede the development of wheeze in childhood: a birth cohort study.

RATIONALE: It is not clear to what extent behavior problems observed in children with asthma antecede asthma development, or are a consequence of the disease. OBJECTIVES: We investigated psychologic factors at age 3 years and subsequent development of wheeze by age 5 in an unselected birth cohort study. Children were recruited prenatally, followed prospectively, and reviewed at age 3 and 5 years. The rate of significant behavior problems at age 3 (above the clinically relevant cut-off on the Eyberg Child Behavior Inventory) was compared between children who had never wheezed (n = 397) and those developing late-onset wheezing (after age 3 years; n = 39). Late-onset wheezers were more likely to be above cut-offs for behavior problems at 3 years (before wheeze onset), compared with children who never wheezed, on Intensity (23.1% vs. 6.0%, p < 0.001) and Problem scores (10.8% vs. 1.3%, p < 0.001). Families of late-onset wheezers had poorer scores on family functioning variables, but we found no evidence of increased anxiety or depression scores in parents. In the multivariate analysis, significant and independent associates of late-onset wheeze were as follows: maternal asthma (odds ratio [OR] 5.4, 95% confidence intervals [CI] 2.1-13.8, p < 0.001), maternal smoking when child was 3 years (OR 3.3, CI 1.2-8.7, p = 0.02), expressiveness (OR 0.71, CI 0.55-0.9, p = 0.005), and significant behavior problems at age 3 years (OR 3.5, CI 1.2-9.9, p = 0.02). CONCLUSIONS: Behavior problems in early life are associated with increased risk of subsequent development of wheeze.

Age of Onset↗
PubMed2004

Wheeze phenotypes and lung function in preschool children.

Distinct phenotypes can be identified in childhood wheezing illness. Within the context of a birth cohort study, we investigated the association between preschool lung function and phenotypes of wheeze. From parentally reported history of wheeze (interviewer-administered questionnaire, age 3 and 5 years), children were classified as never wheezers, transient early wheezers, late-onset wheezers, or persistent wheezers. Lung function (specific airway resistance [sRaw]; kPa/second) was assessed at age 3 (n = 463) and 5 years (n = 690). Persistent wheezers had markedly poorer lung function compared with other groups. In children who had wheezed by age 3, the risk of persistent wheeze increased with increased sRaw (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.3-22.0; p = 0.02). In a multivariate model, increasing sRaw (OR 5.5, 95% CI 1.2-25.9; p = 0.03) and the child's sensitization (OR 2.8, 95% CI 1.3-5.8; p = 0.008) were significant independent predictors of persistent wheezing. We found no association between lung function at age 3 and late-onset wheeze in children who had not wheezed previously (OR 0.6, 95% CI 0.07-5.3; p = 0.64). In conclusion, poor lung function at age 3 predicted the subsequent persistence of symptoms in children who had wheezed within the first 3 years, but was not associated with the onset of wheeze after age 3 in children who had not wheezed previously.

Age Factors↗
PubMed2004

Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years.

We investigated whether environmental control during pregnancy and early life affects sensitization and lung function at the age of 3 years. High-risk children (n = 251) were prenatally randomized to stringent environmental control (active) or no intervention (control). Questionnaires, skin testing, IgE, and specific airway resistance (sRaw) measurement were completed at the age of 3 years. Children in the active group were significantly more frequently sensitized compared with control subjects (at least one allergen by skin tests: risk ratio, 1.61; 95% confidence interval [CI], 1.02-2.55; p = 0.04; mite by IgE: risk ratio, 2.85; 95% CI, 1.02-7.97; p = 0.05). However, sRaw was significantly better in the active group (kiloPascal/second, geometric mean [95% CI]: 1.05 [1.01-1.10] vs. 1.19 [1.13-1.25], p < 0.0001, active vs. control). Maximal flow at functional residual capacity was measured using rapid thoracic compression at the age of 4 weeks in a subgroup. Prospective lung function data (at infancy and 3 years) were obtained in 32 children (14 active and 18 control). There was no difference in infant lung function between the groups, but at 3 years, sRaw was significantly lower in the active compared with control children (p = 0.003). Stringent environmental control was associated with increased risk of mite sensitization but better results for some measurements of lung function in high-risk children at the age of 3 years.

Allergens↗
PubMed2004

Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens.

OBJECTIVE: To investigate the effect of pet ownership and exposure to indoor allergens on lung function in 3-year-old children. DESIGN: Birth cohort study. SETTING: Community. PARTICIPANTS: Children recruited prenatally and followed prospectively to age 3 years. MAIN OUTCOME MEASURES: Specific airway resistance (sRaw) (measured with body plethysmograph) at age 3 years; skin-prick tests; data on cat and dog ownership collected prospectively; allergen levels measured in dust collected from homes (high exposure defined as mite allergens >2 microg/g in mattress, and dog >10 microg/g and cat >8 microg/g allergens on the living room floor). RESULTS: There was no effect of cat or dog ownership at birth or age 3 years on lung function, and no association between lung function and mite, dog, or cat allergen exposure. Sensitized children exposed to high levels of sensitizing allergen had significantly poorer lung function (n = 49, sRaw kiloPascal per second [kPa/s]; geometric mean [GM], 1.20; 95% confidence interval [CI], 1.13-1.28) than children who were not sensitized and not exposed (n = 114; GM, 1.08; 95% CI, 1.04-1.12); not sensitized, but exposed (n = 282; GM, 1.07; 95% CI, 1.05-1.10); or sensitized and not exposed (n = 53; GM, 1.12; 95% CI, 1.06-1.18; P = .005). In a multivariate model, independent significant associates of lung function were maternal and paternal asthma, and the combination of sensitization and exposure to sensitizing allergen, with significant interaction between them. Lung function was substantially worse in sensitized and highly exposed children with both asthmatic parents (GM, 2.23; 95% CI, 1.68-2.97), compared with those with neither (GM, 1.09; 95% CI, 1.04-1.16) or just 1 of these features. CONCLUSIONS: Pet ownership, sensitization without exposure, or exposure in nonsensitized individuals have no effect on lung function. However, the combination of specific sensitization and exposure to sensitizing allergen is associated with significantly poorer lung function in early life.

Air Pollution, Indoor↗
PubMed2004

Allergen avoidance in the primary prevention of asthma.

PURPOSE OF REVIEW: Six primary prevention studies trialing environmental modifications to reduce asthma in children have published results of clinical outcomes. All are still in progress. RECENT FINDINGS: In the Isle of Wight study, mite and food avoidance were evaluated to age 9 months. At 8 years, children in the active group had less current wheeze, wheeze with bronchial hyperresponsiveness and atopy (P < or = 0.05). The Canadian Primary Prevention Study examined avoidance of inhalant and food allergens. At 1 year there was a reduction in probable asthma and rhinitis in the active group. The Study on the Prevention of Allergy in Children in Europe tested avoidance of inhalant and food allergens. At 1 year there was less atopy and sensitization to mites in the active group. In the Childhood Asthma Prevention Study both mite avoidance and a dietary supplement of omega 3 fatty acids were analysed in a factorial design. At age 18 months, children in the dietary intervention group had significantly less wheeze. Eczema was more common amongst children using the mite avoidance measures. The Prevention and Incidence of Asthma and Mite Allergy Study is a placebo-controlled study of mite avoidance. At 2 years, there was a small reduction in nocturnal cough without a cold in the active group. The Manchester Asthma and Allergy Study included stringent environmental control. At 1 year prescribed medication for wheeze and wheeze with shortness of breath were significantly less common in the active group than the control group. SUMMARY: Although initial results look promising, further follow up of the ongoing cohorts is required before any recommendations can be made within the public health context.

Allergens↗