Childhood Asthma in Urban Settings Leadership Center Administrative Supplement for Genotyping Yr4

University Of Wisconsin-Madison, Madison WI

Investigators

Linked publications & trials

Abstract

Contributions of Genetics and DNAm to Phenotypes, Severity & Treatment Response in Urban Children Aim 1. To utilize the novel Asthma&Allergy Array to identify DNAm patterns in blood that link genetics and environmental exposures to the expression of asthma phenotypes in urban children in the APIC study. Rationale: Epigenetic analyses provide a critical link between genetics and environmental exposures in the expression of disease. DNAm is the most common epigenetic mark and methylation levels at CpG sites are influenced by exposures (environment), genetic variation, or both. Importantly, DNAm can mediate the effects of both genetic and environmental risk factors on health outcomes. Carole Ober and colleagues developed the novel Asthma&Allergy array through a study of nasal epithelium from URECA and Childhood Origins of Asthma (COAST) birth cohort participants. Assessment of DNAm in blood, nasal brush, and sputum samples from the Asthma Phenotypes in the Inner City (APIC) study holds great potential to identify potential mechanisms by which various environmental exposures (microbial, allergens, pollutants, etc) contribute to the expression of various respiratory phenotypes such as difficult vs. easy to control asthma and the APIC phenotypes described by Zoratti et al. This provides a unique opportunity to explore how epigenetic patterns are differentially related to asthma phenotypes (such as the T2-low cluster B). By including the nasal and sputum samples, which are available for a subset of the population, we can compare and contrast these relationships across compartments (blood, upper and lower airway). Preliminary Data: Using an empirical Bayes approach to factor analysis and the Asthma&Allergy DNAm array, we recently defined in children three factors comprised of between 6,188 and 659 CpGs from nasal brush samples that are associated with allergic phenotypes in URECA. The genes that are correlated with these DNAm-defined factors are significantly enriched in networks downstream of IFNG and IRF9 (factor 5), SEPTIN1 and BBS1 (factor 9), and TSLP, IL4, IL13, and STAT3 (factor 16). Based on the direction of gene effects in these networks, the factor 5 genes suggest “impaired microbial response”, the factor 8 genes suggest “impaired barrier function”, and the factor 16 genes suggest “activated T2 immune response”. Study Design: In this study, we propose to use the Asthma&Allergy array to analyze DNAm in blood samples from more than 500 APIC children. Additionally, we will analyze DNAm in sputum and nasal brush samples from a subset of these children. We will then assess patterns of DNAm and their association to asthma phenotypes and severity, as well as environmental exposures assessed in APIC. Further, we can integrate this data with the whole genome sequencing previously performed to assess meQTLs and understand the role of genetic variation in DNAm patterns. Anticipated Results & Interpretation: We anticipate that we will identify DNAm patterns that mediate the contributions of genetics and environmental exposures to the expression of respiratory phenotypes and asthma severity in urban children in APIC. Aim 2. To genotype urban children in the ACE, ICATA and PROSE clinical trials, inadequately represented in genetic studies of asthma to date, in order to assess contributions of genetics to disease severity and treatment response. Rationale. While large GWAS studies have been performed in asthma, black and Hispanic participants have been woefully underrepresented in these studies. We have previously genotyped APIC, URECA, MUPPITS-1, and MUPPITS-2. We have stored DNA available from the ACE, ICATA and PROSE clinical trials. Generating genotype data from these prior studies is a unique opportunity to further address the underrepresentation of these children in GWAS studies of asthma. Further, it will provide the opportunity to examine many important questions, such as the impact of genotype on biologic treatment response (omalizumab) the relationships between genotype and disease severity across ICAC studies. and gene by environment interactions. Preliminary data and Experimental Design. Genotyping of the APIC and URECA studies has led to multiple publications. Analyses are ongoing of the recently generated MUPPITS-1 and -2 genotype data. We will use the same Illumina genotyping array that was employed for the genotyping of MUPPITS-1 and -2. Anticipated results and interpretation. We anticipate that we will identify SNPs and polygenic risk scores associated with the expression of asthma phenotypes, therapeutic responses, and interacting with environmental exposures important in urban environments.