The nasal methylome and childhood atopic asthma.

BACKGROUND: Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. OBJECTIVE: We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. METHODS: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). RESULTS: We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively (P < 2.8 × 10-6 for differentially methylated regions and P < 7.8 × 10-10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. CONCLUSIONS: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

Exploring racial differences in IgE-mediated food allergy in the WHEALS birth cohort.

BACKGROUND: Suspected food allergies are the cause of more than 200,000 visits to the emergency department annually. Racial differences in the prevalence of food allergy have also been reported, but the evidence is less conclusive. Researchers continue to struggle with the identification of food allergy for epidemiologic studies. OBJECTIVE: To explore racial differences in IgE-mediated food allergy (IgE-FA) in a birth cohort. METHODS: We used a panel of board-certified allergists to systematically identify IgE-FA to egg, milk, or peanut in a multiethnic birth cohort in which patient medical history, patient symptoms, and clinical data were available through 36 months of age. RESULTS: Of the 590 infants analyzed, 52.9% were male and 65.8% African American. Sensitization (serum specific IgE >0.35 IU/mL) to the food allergens was significantly higher for African American children compared with non-African American children as has been previously reported. No statistically significant racial/ethnic differences in IgE-FA were observed; however, a higher proportion of African American children were designated as having peanut allergy, and the percentage of African American children with an IgE level greater than 95% predictive decision points for peanut was 1.7% vs 0.5% for non-African American children. With the use of logistic regression, race/ethnicity was not significantly associated with IgE-FA (adjusted odds ratio, 1.12; 95% confidence interval, 0.58-2.17; P = .75) but was associated with sensitization to more than 1 of the food allergens (adjusted odds ratio, 1.80; 95% confidence interval, 1.22-2.65; P = .003). CONCLUSION: We did not observe an elevated risk of IgE-FA for African American children, although established differences in sensitization were observed. Racial/ethnic differences in sensitization must be taken into consideration when investigating disparities in asthma and allergy.

DNA methylation and childhood asthma in the inner city.

BACKGROUND: Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important to define epigenetic alterations in asthmatic populations. OBJECTIVE: We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma. METHODS: We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients. RESULTS: Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1. Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively (P < 6 × 10(-12) for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL4 and ST2). Methylation marks involved in T-cell maturation (RUNX3), TH2 immunity (IL4), and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city. CONCLUSIONS: Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma.

Transforming growth factor beta (TGFß1) in breast milk and indicators of infant atopy in a birth cohort.

BACKGROUND: The infant gut's ability to suppress immunologic reactions to food proteins could be influenced by levels of TGFß in breast milk. We hypothesized that lower levels of TGFß(1) in the breast milk (BM) of mothers in the WHEALS birth cohort are associated with atopy at infant age 2-3 yrs. METHODS: We used data collected during infancy in addition to the results of skin prick tests (SPT+) and measures of specific IgE >0.35 IU/ml (spIgE) to milk, egg, and peanut at infant age 2-3 years. Infants were classified as food allergic (FA) based on parental report of infant symptoms/diagnoses and information from clinical assessments. RESULTS: Data for 304 cohort members were analyzed. Among non-black infants, BM-TGFß(1) was lower for those classified as FA (vs. no FA) and those SPT+ (vs., SPT-), geometric mean = 1100 pg/ml vs. 1417pg/ml, p = 0.081; and 1100 pg/ml vs. 1415pg/ml, p = 0.064, respectively. Among infants of non-atopic mothers, BM-TGFß(1) was lower for those with elevated (vs. not elevated) sIgE, geometric mean = 1347 pg/ml vs. 1651 pg/ml, p = 0.047. Using logistic regression, adjusted odds ratios describing the association of BM-TGFß1 to the presence of atopic indicators in the infant were in the hypothesized direction only for non-black infants of non-atopic mothers: aORs for FA, sIgE and SPT+ were 0.08, 0.34, and 0.26 respectively; p = 0.091, 0.13, and 0.23. CONCLUSION: Immune benefit of BM-TGFß(1) could inform prevention strategies. Evidence of an association appears greatly influenced by infant race and maternal atopy. More research can determine if these relationships represent a modifiable risk factor for the development of food allergy in certain subgroups.

Analysis of allergen specific IgE cut points to cat and dog in the Childhood Allergy Study.

BACKGROUND: The application of a single allergen specific IgE (sIgE) cut point, such as 0.35 kU/L, to determine sensitization for all allergens may be suboptimal. OBJECTIVES: To analyze self-reported symptoms suggestive of dog and cat allergy in relation to the test performance characteristics of low level, but reliably detectable, sIgE and to compare these cut points to the traditional 0.35-kU/L cut point. METHODS: Interviews and blood samples were collected among 564 young adult participants of a general risk birth cohort. Data collected from the participants' parents were analyzed as validation populations. A history of symptoms consistent with allergy on exposure to pets was obtained by standardized questionnaire. Allergen sIgE levels for dog and cat were evaluated with Pharmacia CAP. Receiver operating characteristic curves were constructed and the performance characteristics of the traditional sIgE cut point of 0.35 kU/L were compared with cut points as low as 0.1 kU/L. RESULTS: Using the Youden J criteria, based on the highest sum of sensitivity and specificity for a diagnostic test, cut points of 0.12 kU/L for cat and 0.2 kU/L for dog were identified as performing optimally among the participant population. In 2 validation populations, consisting of the participants' mothers and fathers, the performance of these alternative cut points were superior or similar to the traditional 0.35-kU/L sIgE level. CONCLUSIONS: Accurately measured sIgE at levels approaching the lower limit of detection of current assays may be useful in confirming sensitization. Optimal clinical application of these tests will continue to require careful integration of the result and the strength of the patient's history.

Are specific allergen sensitivities inherited?

A family history of an allergic condition is a well-accepted risk factor for the development of an allergic condition in an individual, particularly for allergic disorders such as asthma, eczema, and allergic rhinitis. However, the question of whether specific allergen sensitization is inherited requires a complicated answer, as environmental exposure plays an important role in the development of allergen-specific IgE. This article summarizes the findings of recent studies in the literature regarding what is known about the inheritance of specific allergens. Overall, properly collected and analyzed data appear to both support and refute the hypothesis that specific allergen sensitization is inherited, even when attempting to account for the complexities of varying study methodologies and the evaluation of diverse populations and communities.

Specific allergic sensitization in parents and their 18-year-old offspring in the Suburban Detroit Childhood Allergy Study.

BACKGROUND: Allergic sensitization is increased among offspring of sensitized parents. OBJECTIVE: We sought to evaluate whether 18-year-old offspring are likely to have the same allergic sensitizations as their parents. METHODS: Eighteen-year-old participants in an unselected birth cohort and their parents were tested for total and increased (>0.35 kU/L) levels of allergen-specific IgE to 6 allergens: Dermatophagoides farinae, dog, cat, grass, ragweed, and Alternaria alternata. RESULTS: In 316 parent-teen triads parental sensitization to any of 6 allergens was associated with teen sensitization to any of those same allergens. An increased risk of matched sensitization (ie, a teen has an increased risk of being sensitized to the same specific allergen as their parent) was found after adjusting for the spouse's sensitivities and adjusting for other allergens (ie, the parent had an allergic sensitization but not to the particular allergen under analysis). Risk of maternal matched sensitization with their teen to cat (adjusted odds ratio [aOR], 2.1; 95% CI, 1.0-4.5), grass (aOR, 2.5; 95% CI, 1.2-5.2), and A alternata (aOR, 2.4; 95% CI, 1.1-5.5) was increased when compared with that seen in teens without parental allergen-specific sensitization. Similarly, a higher than expected risk of paternal matched sensitization with their teen to dog (aOR, 2.7; 95% CI, 1.3-5.9), D farinae (aOR, 2.7; 95% CI, 1.4-5.1), and grass (aOR, 2.7; 95% CI, 1.5-5.9) was observed. CONCLUSION: Parental allergen-specific IgE increases the likelihood of sensitization to the same allergen in young adult offspring.