Rana Tawil Misiak

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.

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.

Transforming growth factor beta (TGFβ1) in breast milk and indicators of infant atopy in a birth cohort.

The infant guts ability to suppress immunologic reactions to food proteins could be influenced by levels of TGFβ in breast milk. We hypothesized that lower levels of TGFβ1 in the breast milk (BM) of mothers in the WHEALS birth cohort are associated with atopy at infant age 2–3 yrs.

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 spouses 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.

Using a physician panel to estimate food allergy prevalence in a longitudinal birth cohort

The incidence of immunoglobulin E-mediated food allergy (IgE-FA) has increased in the US and Europe, likely due to a complex interplay between biologic, genetic and environmental factors.1-4 The estimated prevalence (95% Confidence Interval) of allergy to milk, egg, and peanut among US 0-2 year olds is 2.0% (1.6-2.4), 1.0% (0.7, 1.3), and 1.4% (1.1-1.8), respectively.5 Determining the prevalence of IgE-FA status for epidemiologic studies is challenging.6 Self-report may result in overestimates due to the inability of respondents to distinguish food intolerance from IgE-FA.7, 8 The double-blind placebo controlled food challenge (DBPCFC), while a gold standard for diagnosis of IgE-FA, is seldom feasible for large, epidemiologic studies. It is costly in terms of materials and staff and there is risk to the patient.9-11 The use of predictive decision points for specific IgE (sp-IgE) and skin prick tests (SPT) that predict clinical reactivity with > 95% certainty also have limitations and do not incorporate patient symptoms.12, 13 Even using sp-IgE as an outcome in research is problematic, since only 40% of persons who are sensitized to food allergens will respond to a DBPCFC.14 The challenge for advancing epidemiologic investigations in IgE-FA is to combine physician expertise with clinical assessments, medical history and self-report of symptoms. We describe the process of establishing a physician panel to systematically review data from infants enrolled in a birth cohort. Physicians then classified them according to the presence of IgE-FA.

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.

DNA Methylation Changes in Nasal Epithelia Are Associated with Allergic Asthma in the Inner City

Correspondence and requests for reprints should be addressed to Donata Vercelli, M.D., Graduate Program in Cellular and Molecular Medicine, Arizona Respiratory Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721. E-mail: donata@email.arizona.edu Ann Am Thorac Soc Vol 13, Supplement 1, p S99, Mar 2016 Copyright