BackgroundThe aim of this study was to explore the natural history of peanut allergy in childhood... more BackgroundThe aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England.MethodsThe FAIR birth cohort was established on the Isle of Wight (UK) between 2001 and 2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history.ResultsIn the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1, 2, 3 and 10 years, respectively. At 10 years of age, 12 of 828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first 10 years of life, 13 of 9...
International Journal of Epidemiology, Jul 8, 2020
Positive skin test was defined as a mean wheal diameter of 3 mm or more to a panel of 12 common a... more Positive skin test was defined as a mean wheal diameter of 3 mm or more to a panel of 12 common allergens.
Background: The aim of this study was to explore the natural history of peanut allergy in childho... more Background: The aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England. Methods: The FAIR birth cohort was established on the Isle of Wight (UK) between 2001-2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) Birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history. Results: In the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1,2,3 and 10 years respectively. At 10 years of age, 12/828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first ten years of life, 13/934 (1.4%) children were diagnosed with peanut allergy. In the IOW cohort, 6/1034 (0.58%) were diagnosed with peanut allergy at 10 years. We found no significant differences between the FAIR and the IOW birth cohort for any of the time points studied. 3 Conclusion: Peanut allergy appears to be stable over the first ten years of life in our cohorts. There was no significant difference in peanut sensitization or clinical peanut allergy between 1989 and 2001.
The Journal of Allergy and Clinical Immunology, Feb 1, 2014
RATIONALE: Wheat allergy is a growing problem in Asian countries. Factors associated the diseases... more RATIONALE: Wheat allergy is a growing problem in Asian countries. Factors associated the diseases from western studies may not apply to the population because of genetic, geographical and dietary differences. Early life circumstances may affect development of sensitization and food allergy. We aimed to determine prenatal and postnatal factors associated with wheat allergy. METHODS: Using case-control design, 47 infants with IgE-mediated wheat allergy and 188 gender and age matched controls were enrolled. Personal histories and associated factors were analysed. RESULTS: Ninety-two percent of wheat-allergic infants had symptoms on first exposure, suggested the role of sensitization intrauterine or via breast milk. Anaphylaxis occurred in 19% of subjects. Parental atopic histories and high socioeconomic status significantly increased the risk of wheat allergy. IgE-mediated wheat allergy was independently associated with maternal wheat consumption during pregnancy (bread>3 pieces per week, adjusted odds ratio, 3.7; 95% confidence interval, 1.8 to 7.5;P50.001), and breast feeding beyond 6 months (adjusted odds ratio, 2.3; 95 % confidence interval, 1.1 to 4.8;P50.03). Delayed wheat introduction after 6 months of age had trend toward the association with IgE positivity to wheat (adjusted odds ratio 1.8; 95 % confidence interval, 0.9 to 3.9;P50.09). CONCLUSIONS: Several factors during prenatal and early life period associated with the risk of IgE-mediated wheat allergy. Our findings demonstrated that genetic predisposition and socioeconomic status strongly increased risk of wheat allergy. Maternal consumption of wheat during pregnancy and prolonged breast feeding were significantly associated with the disease. Developing the strategies to prevent wheat allergy requires consideration of all these factors.
Background: Patients often report adverse reactions to wheat. Interpretation of sensitization to ... more Background: Patients often report adverse reactions to wheat. Interpretation of sensitization to wheat pollen and flour with/without sensitization to grass pollen is a clinical problem. Aim: We set out to determine the prevalence of wheat allergy in a birth cohort (10/11 year olds) and investigate the usefulness of performing skin prick tests (SPT), specific IgE tests and component resolved diagnostics to wheat pollen and flour. Methods: The Food Allergy and Intolerance Research (FAIR) birth cohort included babies born on the Isle of Wight (UK) between September 2001-August 2002 (n = 969). Children were followed up at 1, 2, 3 and 10/11 years. 588 children had SPTs to wheat pollen and grass during the 10 year follow-up. 294 children underwent further SPT to wheat flour and 246 had specific IgE testing to wheat and grass. Results: Eight children underwent oral food challenges (OFC). We diagnosed 0.48 % (4/827; 95 % CI 0-1 %) children with wheat allergy based on OFC. 16.3 % (96/588) were sensitized to grass pollen, 13.4 % (79/588) to wheat pollen; 78 % (75/96) sensitized to both. Only one child was sensitized to wheat flour and wheat pollen, but not grass pollen. For specific IgE, 15.0 % (37/246) and 36.2 % (89/246) were sensitized to wheat and grass pollen, with 40.5 % (36/89) sensitized to both. Of the 37 children sensitized to wheat, 3 (8.1 %) were sensitized to omega 5 gliadin, 1 (2.7 %) to wheat lipid transfer protein and 1 to wheat gliadin. Conclusion: Clinicians should be aware of the high level of cross-sensitization when performing tests to wheat and grass pollen i.e. sensitisation to wheat specific IgE and wheat pollen SPT should be assessed in the presence of grass pollen SPT and/or specific IgE.
Background: To investigate the intergenerational effects of grandmaternal smoking during pregnanc... more Background: To investigate the intergenerational effects of grandmaternal smoking during pregnancy (GMSDP) on the DNA methylation of grandchildren. Methods: Data from the Isle of Wight birth cohort with information regarding GMSDP and DNA methylation profiling at the birth of grandchildren (n = 161) were used. Differentially methylated CpG sites related to GMSDP were identified using testing–training screening, analysis of variance and multivariate analysis of covariance. The association between identified CpG sites and expression levels of neighboring genes was tested by linear regression. Results: Twenty-three CpG sites were differentially methylated in grandchildren because of GMSDP, and eight of these were associated with expression levels of 13 neighboring genes. Conclusion: GMSDP has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.
Background: Evidence suggests that prenatal exposure to n-3 long-chain polyunsaturated fatty acid... more Background: Evidence suggests that prenatal exposure to n-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces the incidence of allergic disease in children. LCPUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by the FADS1/2 and ELOVL5 genes. DNA methylation regulates gene activity and fatty acid supplementation could alter DNA methylation (DNA-M) at these genes. We investigated whether DNA-M and expression of the FADS1/2 and ELOVL5 genes were associated with allergy in children and gestational fish intake. We studied 170 participants from the Isle of Wight 3rd Generation Cohort, UK. Phenotype data and exposure was assessed by questionnaires. Genome-wide DNA-M in cord blood samples was quantified using the Illumina Infinium HumanMethylation450 and EPIC Beadchips. Five SNPs (single-nucleotide polymorphisms) in the FADS gene cluster and one SNP in ELOVL5 were genotyped in offspring. FADS gene expression in offspring cord blood was determined. Results: Gestational fish intake was significantly associated with increased methylation of cg12517394 (P = 0.049), which positively correlated with FADS1 mRNA levels (P = 0.021). ELOVL5 rs2397142 was significantly associated with eczema (P = 0.011) and methylation at cg11748354 and cg24524396 (P < 0.001 and P = 0.036, respectively). Gestational fish intake was strongly associated with elevated DNA-M at cg11748354 and cg24524396 (P = 0.029 and P = 0.002, respectively) and reduced ELOVL5 mRNA expression (P = 0.028). Conclusion: The association between induced FADS1/2 and ELOVL5 DNA-M and reduced gene expression due to gestational fish intake provide a mechanistic explanation of the previously observed association between maternal LCPUFA intake and allergy development in early childhood.
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, Jan 26, 2018
To the editor, Multiple tests are available to determine food and aero-allergen sensitization (1,... more To the editor, Multiple tests are available to determine food and aero-allergen sensitization (1,2), but it is unclear if distinct sensitization patterns can be determined by using a combination of three testing modalities; skin prick test (SPT), specific IgE test and component resolved diagnostic tests to characterize or identify certain clinical phenotypes. This is a novel paper utilizing sensitization clusters (SPT, specific IgE tests and component resolved diagnostics) in an unselected cohort of 10/11 year-old children and its association with asthma, eczema, rhinitis and IgE-mediated food allergy. A birth cohort recruited in 2001 (Isle of Wight), was followed up prospectively to 10 years of age (3) (n = 827). At ten years SPT were performed to milk, egg, wheat pollen and flour, cod, sesame, peanut, house dust mite Dermatophagoides pteronyssinus (HDM), cat, grass and birch pollen (ALK-Abello, Hørsholm, Denmark) and lupin (Stallergens). A subset of children (n=246) consented to a blood test, analysed using ImmunoCap (ThermoFisher) using a predefined algorithm: Children were screened using the Fx5 test (milk, egg, wheat, cod, wheat, peanut, soy). Children with a positive screen (> 0.35 kuA/L), specific IgE to these foods were tested. We also tested specific IgE to lupin and sesame. If specific IgE to peanut and wheat were positive, then we tested: Wheat (rTria19, Wheat LTP, Gliadin) and peanut (Ara h1, Ara h2, Ara h3, Ara h8, Ara h9). For aero-allergens, Phadiatop Immunocap including grasses, trees, weeds, cat, dog, mites and molds was used. Those with a positive result were tested for specific IgE (grass, birch, house dust mite or dog, cat). If the specific IgE to grass or birch was positive, we tested for: Grass: Phlp1; Phlp7; Phlp p12; Phlp 5b and Birch (Bet v1 (PR10); Bet v2 (profilin)). Rates of current allergic diseases were measured using the validated International Study of Asthma and Allergies in Childhood questionnaire at the same clinic appointment (4). IgE mediated food allergy was defined as a positive food challenge or a positive SPT (≥3mm) and a convincing clinical history, as previously reported (3). Data was double entered in SPSS versions 20 and 21 and were compared and verified (SPSS Inc, Chicago, USA). Prevalence rates were computed together with 95% confidence intervals (CI). The CI were calculated using the exact CI, computed by the method of Clopper and Pearson. Chi square tests were undertaken to determine differences in those who did and did not consent for tests. Non-parametric cluster analyses were implemented, using the Kmeans approach. Standardized data were utilized in the analyses to reduce potential bias caused by different scales in the data. The scaling was conducted by standardizing with respect to mean (value-mean/standard deviation) for each variable. To determine the number of clusters, for each given number of clusters, we used the ratio between the sum of squares of variation between clusters and the sum of square of total variation. The final number of clusters is determined by maximizing the ratio with an effort to achieve parsimonious clusters. Logistic regressions, expressed as odds ratios (OR) were used to assess the association of hayfever, asthma, eczema, or food allergy with the pattern of allergic sensitization measures, IgE, and CRD. In this analysis, clusters with less than three subjects were deleted from further logistic regression analyses to avoid large uncertainty. Ethical approval for the study was obtained from the NRES South Central-Southampton B Research Ethics Committee (REF 10/H0504/11) and consent/assent obtained. We followed 827, 85% of the original Food Allergy and Research study (FAIR) cohort at 10/11 years of age and of these 827; 246 children (29.75%; 246/827) consented to a blood test: 2.84% (7/246) had peanut allergy, 5.3% (12/246) had an IgE mediated food allergy, (of these 12 children diagnosed food allergy at 10 years of age, 7 children had a positive food challenge at 10 years, the other 5 children had a history of past positive food challenge/reaction on ingestion with sustained sensitization and declined the food challenge). 17.5% (43/246) reported asthma at 10 years, 30.1% reported eczema at 10 years and 37.8% (93/246) reported hayfever at 10 years. Sensitization data are summarized in table 1. Cluster analysis identified nine initial clusters, using 36 selected variables out of 39 in total that were tested. The following three variables were excluded due to missing values: milk SPT, lupin specific IgE and sesame specific IgE. In total, 4 participants having missing values in one or more of the 35 variables were excluded from cluster analyses. In addition, two clusters containing only 2 participants
Introduction: Maternal (M) and grandmaternal (GM) gestational smoking increase the risk of wheeze... more Introduction: Maternal (M) and grandmaternal (GM) gestational smoking increase the risk of wheeze in offspring. The aryl-hydrocarbon receptor repressor (AHRR) is involved in detoxification of tobacco smoke compounds. DNA methylation (DNA-M) at AHRR CpG site cg05575921 is lower on exposure to smoking. Aims: Proof-of-concept showing the role of DNA methylation in transgenerational effects of smoking. Effect of M and GM smoking on methlyation of AHRR cg05575921 in cord blood. Methods: The Isle of Wight birth cohort is an unselected birth cohort 1989-90 ( n =1456), children of the cohort were recruited in a third generation study. Smoking in pregnancy by M and GM during pregnancy was collected prospectively. The effect of gestational smoking on cg05575921 in F 2 cord blood ( n =96) was assessed by linear regression analysis. Results: DNA-M at cg05575921 was hypomethylated with either M or GM gestational smoking, though the effect of both M and GM smoking was greater. Infants exposed to both M and GM smoking had significantly lower cg05575921 methylation than unexposed infants (p= 0.002). Conclusion: Study shows that transgenerational gestational smoking influences cg05575921 methylation, the consequences of gestational smoking may compound across generations. Further studies are needed to confirm the role of epigenetics in transgenerational effects of environmental exposures.
Background: Gestational smoking is associated with eczema and asthma during adolescence. Prior st... more Background: Gestational smoking is associated with eczema and asthma during adolescence. Prior studies have shown that gestational smoking reduces the DNA methylation (DNA-M) of AHRR (Aryl-Hydrocarbon Receptor Repressor) CpG (cytosine-phosphate-guanine) sites. Objective: To assess the interaction of DNA-M of AHRR CpG cg05575921 and gestational smoking for the risk asthma and eczema in boys and girls at age 18. Methods: Blood samples, asthma and eczema status were obtained at age 18 from the Isle of Wight birth cohort, UK. Maternal smoking was ascertained at birth. DNA-M was assessed by Illumina Infinium HumanMethylation450 array. Using linear regression, residuals were calculated by excluding the effect of gestational smoking on DNA-M at cg05575921. Log-linear models were used to test interaction of residuals and gestational smoking with eczema and asthma. Results: At age 18, 10.3% of boys (n=648) and 10.1% of girls (n=653) had eczema if the mother smoked during pregnancy; and 7.8% of boys and 18.0% girls had eczema if the mother did not ( p -value 0.32 in boys; 0.02 in girls). In contrast, for asthma, the respective proportions in the same order were, 11.2% boys (n=643) and 21.4% girls (n=656); and 17.2% boys and 18.9% girls ( p -value 0.08 in boys; 0.49 in girls). The interaction of residuals and gestational smoking was significantly associated with eczema but not with asthma. The relative risk of eczema is 0.4 times lower when methylation of cg05575921 was higher and the mother smoked during pregnancy. Conclusion: AHRR DNA-M may explain the trend of eczema in boys and girls with gestational smoking. Future analysis should explore the pathway by which AHRR is associated with eczema.
Season of birth influences allergy risk, however the biological mechanisms underlying this observ... more 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. 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 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. Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with seas...
Background: The prevalence of allergic diseases are increasing worldwide, emphasizing the need to... more Background: The prevalence of allergic diseases are increasing worldwide, emphasizing the need to elucidate their pathogeneses. The aims of this study were to use a two-stage design to identify DNA methylation levels at cytosine-phosphate-guanine (CpG) sites across the genome associated with atopy and high serum immunoglobulin E (IgE), then to replicate our findings in an independent cohort. Methods: Atopy was assessed via skin prick tests and high serum IgE. Methylation levels were measured from whole blood using the Illumina Infinium HumanMethylation450 BeadChip from 18-year-old women (n = 245) and men (n = 122) in the Isle of Wight birth cohort. After data cleaning and processing, and removing probes with possible single nucleotide polymorphisms, DNA methylation levels from 254,460 CpG sites from the 245 women were subjected to recursive Random Forest feature selection for stage 1. The sites selected from stage 1 were tested in stage 2 for associations with atopy and high IgE levels (>200 kU/L) via logistic regression adjusted for predicted cell-type proportions and sex. Sites significantly associated with atopy in stage 2 underwent replication tests in the independent Swedish birth cohort BAMSE (n = 464). Results: In stage 1, 62 sites were selected, of which 22 were associated with atopy in stage 2 (P-value range 6.5E−9 to 1.4E−5) and 12 associated with high IgE levels (P-value range 1.1E−5 to 7.1E−4) at the Bonferroni adjusted alpha (0.05/62 = 0.0008). Of the 19 available sites, 13 were replicated. Conclusions: We identified 13 novel epigenetic loci associated with atopy and high IgE that could serve as candidate loci for future studies; four were within genes with known roles in the immune response (cg04983687 in the body of ZFPM1, cg18219873 in the 5′UTR of PRG2, cg27469152 in the 3′UTR of EPX, and cg09332506 in the body of COPA).
SummaryBackgroundWhile the prevalence of asthma in children is decreasing or remaining the same, ... more SummaryBackgroundWhile the prevalence of asthma in children is decreasing or remaining the same, time trends in the prevalence of rhinitis in children are not known. Understanding sensitisation trends may help inform about trends in asthma and rhinitis prevalence.ObjectiveTo assess time trends of wheeze, rhinitis and aero‐allergen sensitisation prevalence at 10 years of age, we compared two birth cohorts established 12 years apart. To gain insight into differences in disease prevalence, we assessed association of family history, early life exposures and sensitisation with wheeze and rhinitis in each cohort.MethodsThe IoW (Isle of Wight) and FAIR (Food Allergy and Intolerance Research) unselected birth cohorts were established in 1989 and 2001 respectively in IoW. Identical ISAAC questionnaire and skin prick test data were collected and compared at 10 years of age.ResultsOver the 12‐year period from 2001 to 2012, prevalence of lifetime wheeze, current wheeze and those ever treated fo...
Background: Asthma is characterized by airflow limitation and airway reactivity (AR). Interleukin... more Background: Asthma is characterized by airflow limitation and airway reactivity (AR). Interleukin-13 (IL-13) is involved in the pathogenesis of asthma. Two functional SNPs, rs20541 and rs1800925, of the IL-13 gene (IL13) have been frequently associated with asthma-related lung functions. However, genetic variation alone does not fully explain asthma risk. DNA-methylation (DNA-M) is an epigenetic mechanism that regulates gene expression and can be influenced by both environment and genetic variants. To explore the interplay of prenatal maternal smoking, genetic variants and DNA-M, we used a two-stage model: (1) identifying cytosine phosphate guanine (CpG) sites where DNA-M is influenced by the interaction between genetic variants and maternal smoking during pregnancy (conditional methQTL (methylation quantitative trait loci)); and (2) determining the effect of the interaction between DNA-M of CpG (from stage 1) and SNPs (modifying genetic variants; modGV) on airflow limitation and AR in 245 female participants of the Isle of Wight birth cohort. DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip. Findings: Six CpG sites were analyzed in stage 1. DNA-M at cg13566430 was influenced by interaction of maternal smoking during pregnancy and rs20541. In stage 2, genotype at rs1800925 interacted with DNA-M at cg13566430 significantly affecting airflow limitation (P = 0.042) and AR (P = 0.01). Conclusion: Both genetic variants and environment affect DNA-M. This study supports the proposed two-stage model (methQTL and modGV) to study genetic variants, environment and DNA-M interactions in asthma-related lung function.
Background: The prevalence of asthma in girls increases after puberty. Previous studies have dete... more Background: The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants. Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma. Results: Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P = 0.002, false discovery rate (FDR) adjusted P = 0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P = 0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P = 0.006, FDR adjusted P = 0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA. Conclusion: A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.
BackgroundThe aim of this study was to explore the natural history of peanut allergy in childhood... more BackgroundThe aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England.MethodsThe FAIR birth cohort was established on the Isle of Wight (UK) between 2001 and 2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history.ResultsIn the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1, 2, 3 and 10 years, respectively. At 10 years of age, 12 of 828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first 10 years of life, 13 of 9...
International Journal of Epidemiology, Jul 8, 2020
Positive skin test was defined as a mean wheal diameter of 3 mm or more to a panel of 12 common a... more Positive skin test was defined as a mean wheal diameter of 3 mm or more to a panel of 12 common allergens.
Background: The aim of this study was to explore the natural history of peanut allergy in childho... more Background: The aim of this study was to explore the natural history of peanut allergy in childhood in two birth cohorts from the same geographical region in the South of England. Methods: The FAIR birth cohort was established on the Isle of Wight (UK) between 2001-2002 (n = 969). Children were followed up prospectively, skin prick tested (SPT) to peanut allergens at 1, 2, 3 and 10 years and food challenges performed. The Isle of Wight (IOW) Birth cohort was established in 1989 (n = 1456). SPTs were performed at 1, 2, 4 and 10 years. Peanut allergy was based on positive SPT and a good clinical history. Results: In the FAIR cohort, the prevalence of sensitization to peanut was 0.4%, 2.0%, 2.0% and 2.4% at 1,2,3 and 10 years respectively. At 10 years of age, 12/828 (1.5%) children were diagnosed with peanut allergy. One child (8%) outgrew her peanut allergy between 3 and 10 years and two children (15%) presented with new onset peanut allergy. Over the first ten years of life, 13/934 (1.4%) children were diagnosed with peanut allergy. In the IOW cohort, 6/1034 (0.58%) were diagnosed with peanut allergy at 10 years. We found no significant differences between the FAIR and the IOW birth cohort for any of the time points studied. 3 Conclusion: Peanut allergy appears to be stable over the first ten years of life in our cohorts. There was no significant difference in peanut sensitization or clinical peanut allergy between 1989 and 2001.
The Journal of Allergy and Clinical Immunology, Feb 1, 2014
RATIONALE: Wheat allergy is a growing problem in Asian countries. Factors associated the diseases... more RATIONALE: Wheat allergy is a growing problem in Asian countries. Factors associated the diseases from western studies may not apply to the population because of genetic, geographical and dietary differences. Early life circumstances may affect development of sensitization and food allergy. We aimed to determine prenatal and postnatal factors associated with wheat allergy. METHODS: Using case-control design, 47 infants with IgE-mediated wheat allergy and 188 gender and age matched controls were enrolled. Personal histories and associated factors were analysed. RESULTS: Ninety-two percent of wheat-allergic infants had symptoms on first exposure, suggested the role of sensitization intrauterine or via breast milk. Anaphylaxis occurred in 19% of subjects. Parental atopic histories and high socioeconomic status significantly increased the risk of wheat allergy. IgE-mediated wheat allergy was independently associated with maternal wheat consumption during pregnancy (bread>3 pieces per week, adjusted odds ratio, 3.7; 95% confidence interval, 1.8 to 7.5;P50.001), and breast feeding beyond 6 months (adjusted odds ratio, 2.3; 95 % confidence interval, 1.1 to 4.8;P50.03). Delayed wheat introduction after 6 months of age had trend toward the association with IgE positivity to wheat (adjusted odds ratio 1.8; 95 % confidence interval, 0.9 to 3.9;P50.09). CONCLUSIONS: Several factors during prenatal and early life period associated with the risk of IgE-mediated wheat allergy. Our findings demonstrated that genetic predisposition and socioeconomic status strongly increased risk of wheat allergy. Maternal consumption of wheat during pregnancy and prolonged breast feeding were significantly associated with the disease. Developing the strategies to prevent wheat allergy requires consideration of all these factors.
Background: Patients often report adverse reactions to wheat. Interpretation of sensitization to ... more Background: Patients often report adverse reactions to wheat. Interpretation of sensitization to wheat pollen and flour with/without sensitization to grass pollen is a clinical problem. Aim: We set out to determine the prevalence of wheat allergy in a birth cohort (10/11 year olds) and investigate the usefulness of performing skin prick tests (SPT), specific IgE tests and component resolved diagnostics to wheat pollen and flour. Methods: The Food Allergy and Intolerance Research (FAIR) birth cohort included babies born on the Isle of Wight (UK) between September 2001-August 2002 (n = 969). Children were followed up at 1, 2, 3 and 10/11 years. 588 children had SPTs to wheat pollen and grass during the 10 year follow-up. 294 children underwent further SPT to wheat flour and 246 had specific IgE testing to wheat and grass. Results: Eight children underwent oral food challenges (OFC). We diagnosed 0.48 % (4/827; 95 % CI 0-1 %) children with wheat allergy based on OFC. 16.3 % (96/588) were sensitized to grass pollen, 13.4 % (79/588) to wheat pollen; 78 % (75/96) sensitized to both. Only one child was sensitized to wheat flour and wheat pollen, but not grass pollen. For specific IgE, 15.0 % (37/246) and 36.2 % (89/246) were sensitized to wheat and grass pollen, with 40.5 % (36/89) sensitized to both. Of the 37 children sensitized to wheat, 3 (8.1 %) were sensitized to omega 5 gliadin, 1 (2.7 %) to wheat lipid transfer protein and 1 to wheat gliadin. Conclusion: Clinicians should be aware of the high level of cross-sensitization when performing tests to wheat and grass pollen i.e. sensitisation to wheat specific IgE and wheat pollen SPT should be assessed in the presence of grass pollen SPT and/or specific IgE.
Background: To investigate the intergenerational effects of grandmaternal smoking during pregnanc... more Background: To investigate the intergenerational effects of grandmaternal smoking during pregnancy (GMSDP) on the DNA methylation of grandchildren. Methods: Data from the Isle of Wight birth cohort with information regarding GMSDP and DNA methylation profiling at the birth of grandchildren (n = 161) were used. Differentially methylated CpG sites related to GMSDP were identified using testing–training screening, analysis of variance and multivariate analysis of covariance. The association between identified CpG sites and expression levels of neighboring genes was tested by linear regression. Results: Twenty-three CpG sites were differentially methylated in grandchildren because of GMSDP, and eight of these were associated with expression levels of 13 neighboring genes. Conclusion: GMSDP has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.
Background: Evidence suggests that prenatal exposure to n-3 long-chain polyunsaturated fatty acid... more Background: Evidence suggests that prenatal exposure to n-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces the incidence of allergic disease in children. LCPUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by the FADS1/2 and ELOVL5 genes. DNA methylation regulates gene activity and fatty acid supplementation could alter DNA methylation (DNA-M) at these genes. We investigated whether DNA-M and expression of the FADS1/2 and ELOVL5 genes were associated with allergy in children and gestational fish intake. We studied 170 participants from the Isle of Wight 3rd Generation Cohort, UK. Phenotype data and exposure was assessed by questionnaires. Genome-wide DNA-M in cord blood samples was quantified using the Illumina Infinium HumanMethylation450 and EPIC Beadchips. Five SNPs (single-nucleotide polymorphisms) in the FADS gene cluster and one SNP in ELOVL5 were genotyped in offspring. FADS gene expression in offspring cord blood was determined. Results: Gestational fish intake was significantly associated with increased methylation of cg12517394 (P = 0.049), which positively correlated with FADS1 mRNA levels (P = 0.021). ELOVL5 rs2397142 was significantly associated with eczema (P = 0.011) and methylation at cg11748354 and cg24524396 (P < 0.001 and P = 0.036, respectively). Gestational fish intake was strongly associated with elevated DNA-M at cg11748354 and cg24524396 (P = 0.029 and P = 0.002, respectively) and reduced ELOVL5 mRNA expression (P = 0.028). Conclusion: The association between induced FADS1/2 and ELOVL5 DNA-M and reduced gene expression due to gestational fish intake provide a mechanistic explanation of the previously observed association between maternal LCPUFA intake and allergy development in early childhood.
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, Jan 26, 2018
To the editor, Multiple tests are available to determine food and aero-allergen sensitization (1,... more To the editor, Multiple tests are available to determine food and aero-allergen sensitization (1,2), but it is unclear if distinct sensitization patterns can be determined by using a combination of three testing modalities; skin prick test (SPT), specific IgE test and component resolved diagnostic tests to characterize or identify certain clinical phenotypes. This is a novel paper utilizing sensitization clusters (SPT, specific IgE tests and component resolved diagnostics) in an unselected cohort of 10/11 year-old children and its association with asthma, eczema, rhinitis and IgE-mediated food allergy. A birth cohort recruited in 2001 (Isle of Wight), was followed up prospectively to 10 years of age (3) (n = 827). At ten years SPT were performed to milk, egg, wheat pollen and flour, cod, sesame, peanut, house dust mite Dermatophagoides pteronyssinus (HDM), cat, grass and birch pollen (ALK-Abello, Hørsholm, Denmark) and lupin (Stallergens). A subset of children (n=246) consented to a blood test, analysed using ImmunoCap (ThermoFisher) using a predefined algorithm: Children were screened using the Fx5 test (milk, egg, wheat, cod, wheat, peanut, soy). Children with a positive screen (> 0.35 kuA/L), specific IgE to these foods were tested. We also tested specific IgE to lupin and sesame. If specific IgE to peanut and wheat were positive, then we tested: Wheat (rTria19, Wheat LTP, Gliadin) and peanut (Ara h1, Ara h2, Ara h3, Ara h8, Ara h9). For aero-allergens, Phadiatop Immunocap including grasses, trees, weeds, cat, dog, mites and molds was used. Those with a positive result were tested for specific IgE (grass, birch, house dust mite or dog, cat). If the specific IgE to grass or birch was positive, we tested for: Grass: Phlp1; Phlp7; Phlp p12; Phlp 5b and Birch (Bet v1 (PR10); Bet v2 (profilin)). Rates of current allergic diseases were measured using the validated International Study of Asthma and Allergies in Childhood questionnaire at the same clinic appointment (4). IgE mediated food allergy was defined as a positive food challenge or a positive SPT (≥3mm) and a convincing clinical history, as previously reported (3). Data was double entered in SPSS versions 20 and 21 and were compared and verified (SPSS Inc, Chicago, USA). Prevalence rates were computed together with 95% confidence intervals (CI). The CI were calculated using the exact CI, computed by the method of Clopper and Pearson. Chi square tests were undertaken to determine differences in those who did and did not consent for tests. Non-parametric cluster analyses were implemented, using the Kmeans approach. Standardized data were utilized in the analyses to reduce potential bias caused by different scales in the data. The scaling was conducted by standardizing with respect to mean (value-mean/standard deviation) for each variable. To determine the number of clusters, for each given number of clusters, we used the ratio between the sum of squares of variation between clusters and the sum of square of total variation. The final number of clusters is determined by maximizing the ratio with an effort to achieve parsimonious clusters. Logistic regressions, expressed as odds ratios (OR) were used to assess the association of hayfever, asthma, eczema, or food allergy with the pattern of allergic sensitization measures, IgE, and CRD. In this analysis, clusters with less than three subjects were deleted from further logistic regression analyses to avoid large uncertainty. Ethical approval for the study was obtained from the NRES South Central-Southampton B Research Ethics Committee (REF 10/H0504/11) and consent/assent obtained. We followed 827, 85% of the original Food Allergy and Research study (FAIR) cohort at 10/11 years of age and of these 827; 246 children (29.75%; 246/827) consented to a blood test: 2.84% (7/246) had peanut allergy, 5.3% (12/246) had an IgE mediated food allergy, (of these 12 children diagnosed food allergy at 10 years of age, 7 children had a positive food challenge at 10 years, the other 5 children had a history of past positive food challenge/reaction on ingestion with sustained sensitization and declined the food challenge). 17.5% (43/246) reported asthma at 10 years, 30.1% reported eczema at 10 years and 37.8% (93/246) reported hayfever at 10 years. Sensitization data are summarized in table 1. Cluster analysis identified nine initial clusters, using 36 selected variables out of 39 in total that were tested. The following three variables were excluded due to missing values: milk SPT, lupin specific IgE and sesame specific IgE. In total, 4 participants having missing values in one or more of the 35 variables were excluded from cluster analyses. In addition, two clusters containing only 2 participants
Introduction: Maternal (M) and grandmaternal (GM) gestational smoking increase the risk of wheeze... more Introduction: Maternal (M) and grandmaternal (GM) gestational smoking increase the risk of wheeze in offspring. The aryl-hydrocarbon receptor repressor (AHRR) is involved in detoxification of tobacco smoke compounds. DNA methylation (DNA-M) at AHRR CpG site cg05575921 is lower on exposure to smoking. Aims: Proof-of-concept showing the role of DNA methylation in transgenerational effects of smoking. Effect of M and GM smoking on methlyation of AHRR cg05575921 in cord blood. Methods: The Isle of Wight birth cohort is an unselected birth cohort 1989-90 ( n =1456), children of the cohort were recruited in a third generation study. Smoking in pregnancy by M and GM during pregnancy was collected prospectively. The effect of gestational smoking on cg05575921 in F 2 cord blood ( n =96) was assessed by linear regression analysis. Results: DNA-M at cg05575921 was hypomethylated with either M or GM gestational smoking, though the effect of both M and GM smoking was greater. Infants exposed to both M and GM smoking had significantly lower cg05575921 methylation than unexposed infants (p= 0.002). Conclusion: Study shows that transgenerational gestational smoking influences cg05575921 methylation, the consequences of gestational smoking may compound across generations. Further studies are needed to confirm the role of epigenetics in transgenerational effects of environmental exposures.
Background: Gestational smoking is associated with eczema and asthma during adolescence. Prior st... more Background: Gestational smoking is associated with eczema and asthma during adolescence. Prior studies have shown that gestational smoking reduces the DNA methylation (DNA-M) of AHRR (Aryl-Hydrocarbon Receptor Repressor) CpG (cytosine-phosphate-guanine) sites. Objective: To assess the interaction of DNA-M of AHRR CpG cg05575921 and gestational smoking for the risk asthma and eczema in boys and girls at age 18. Methods: Blood samples, asthma and eczema status were obtained at age 18 from the Isle of Wight birth cohort, UK. Maternal smoking was ascertained at birth. DNA-M was assessed by Illumina Infinium HumanMethylation450 array. Using linear regression, residuals were calculated by excluding the effect of gestational smoking on DNA-M at cg05575921. Log-linear models were used to test interaction of residuals and gestational smoking with eczema and asthma. Results: At age 18, 10.3% of boys (n=648) and 10.1% of girls (n=653) had eczema if the mother smoked during pregnancy; and 7.8% of boys and 18.0% girls had eczema if the mother did not ( p -value 0.32 in boys; 0.02 in girls). In contrast, for asthma, the respective proportions in the same order were, 11.2% boys (n=643) and 21.4% girls (n=656); and 17.2% boys and 18.9% girls ( p -value 0.08 in boys; 0.49 in girls). The interaction of residuals and gestational smoking was significantly associated with eczema but not with asthma. The relative risk of eczema is 0.4 times lower when methylation of cg05575921 was higher and the mother smoked during pregnancy. Conclusion: AHRR DNA-M may explain the trend of eczema in boys and girls with gestational smoking. Future analysis should explore the pathway by which AHRR is associated with eczema.
Season of birth influences allergy risk, however the biological mechanisms underlying this observ... more 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. 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 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. Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with seas...
Background: The prevalence of allergic diseases are increasing worldwide, emphasizing the need to... more Background: The prevalence of allergic diseases are increasing worldwide, emphasizing the need to elucidate their pathogeneses. The aims of this study were to use a two-stage design to identify DNA methylation levels at cytosine-phosphate-guanine (CpG) sites across the genome associated with atopy and high serum immunoglobulin E (IgE), then to replicate our findings in an independent cohort. Methods: Atopy was assessed via skin prick tests and high serum IgE. Methylation levels were measured from whole blood using the Illumina Infinium HumanMethylation450 BeadChip from 18-year-old women (n = 245) and men (n = 122) in the Isle of Wight birth cohort. After data cleaning and processing, and removing probes with possible single nucleotide polymorphisms, DNA methylation levels from 254,460 CpG sites from the 245 women were subjected to recursive Random Forest feature selection for stage 1. The sites selected from stage 1 were tested in stage 2 for associations with atopy and high IgE levels (>200 kU/L) via logistic regression adjusted for predicted cell-type proportions and sex. Sites significantly associated with atopy in stage 2 underwent replication tests in the independent Swedish birth cohort BAMSE (n = 464). Results: In stage 1, 62 sites were selected, of which 22 were associated with atopy in stage 2 (P-value range 6.5E−9 to 1.4E−5) and 12 associated with high IgE levels (P-value range 1.1E−5 to 7.1E−4) at the Bonferroni adjusted alpha (0.05/62 = 0.0008). Of the 19 available sites, 13 were replicated. Conclusions: We identified 13 novel epigenetic loci associated with atopy and high IgE that could serve as candidate loci for future studies; four were within genes with known roles in the immune response (cg04983687 in the body of ZFPM1, cg18219873 in the 5′UTR of PRG2, cg27469152 in the 3′UTR of EPX, and cg09332506 in the body of COPA).
SummaryBackgroundWhile the prevalence of asthma in children is decreasing or remaining the same, ... more SummaryBackgroundWhile the prevalence of asthma in children is decreasing or remaining the same, time trends in the prevalence of rhinitis in children are not known. Understanding sensitisation trends may help inform about trends in asthma and rhinitis prevalence.ObjectiveTo assess time trends of wheeze, rhinitis and aero‐allergen sensitisation prevalence at 10 years of age, we compared two birth cohorts established 12 years apart. To gain insight into differences in disease prevalence, we assessed association of family history, early life exposures and sensitisation with wheeze and rhinitis in each cohort.MethodsThe IoW (Isle of Wight) and FAIR (Food Allergy and Intolerance Research) unselected birth cohorts were established in 1989 and 2001 respectively in IoW. Identical ISAAC questionnaire and skin prick test data were collected and compared at 10 years of age.ResultsOver the 12‐year period from 2001 to 2012, prevalence of lifetime wheeze, current wheeze and those ever treated fo...
Background: Asthma is characterized by airflow limitation and airway reactivity (AR). Interleukin... more Background: Asthma is characterized by airflow limitation and airway reactivity (AR). Interleukin-13 (IL-13) is involved in the pathogenesis of asthma. Two functional SNPs, rs20541 and rs1800925, of the IL-13 gene (IL13) have been frequently associated with asthma-related lung functions. However, genetic variation alone does not fully explain asthma risk. DNA-methylation (DNA-M) is an epigenetic mechanism that regulates gene expression and can be influenced by both environment and genetic variants. To explore the interplay of prenatal maternal smoking, genetic variants and DNA-M, we used a two-stage model: (1) identifying cytosine phosphate guanine (CpG) sites where DNA-M is influenced by the interaction between genetic variants and maternal smoking during pregnancy (conditional methQTL (methylation quantitative trait loci)); and (2) determining the effect of the interaction between DNA-M of CpG (from stage 1) and SNPs (modifying genetic variants; modGV) on airflow limitation and AR in 245 female participants of the Isle of Wight birth cohort. DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip. Findings: Six CpG sites were analyzed in stage 1. DNA-M at cg13566430 was influenced by interaction of maternal smoking during pregnancy and rs20541. In stage 2, genotype at rs1800925 interacted with DNA-M at cg13566430 significantly affecting airflow limitation (P = 0.042) and AR (P = 0.01). Conclusion: Both genetic variants and environment affect DNA-M. This study supports the proposed two-stage model (methQTL and modGV) to study genetic variants, environment and DNA-M interactions in asthma-related lung function.
Background: The prevalence of asthma in girls increases after puberty. Previous studies have dete... more Background: The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants. Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma. Results: Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P = 0.002, false discovery rate (FDR) adjusted P = 0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P = 0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P = 0.006, FDR adjusted P = 0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA. Conclusion: A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.
Uploads
Papers by Veeresh Patil