Recent Past Projects

• The Olmsted County Minnesota Air Quality Study [The OMAQ Study.]

• Children's Air Pollution Study [CAPS]
• Children's Air Pollution Study [CAPS]

Asthma is the most common chronic illness in childhood and it is widely recognized that there is a major genetic component to asthma susceptibility. Previous studies of the entire genome have identified common variants in more than 15 genes significantly associated with asthma or related phenotypes. While the majority of these findings have been replicated they account for only a small portion of the genetic contribution to asthma. Our goal is to now find genetic variants that are rare in the population but may substantially contribute to the genetics of asthma. Here, we hypothesize a model whereby individual families are segregating “family-specific” mutations contributing to asthma susceptibility. We hypothesize that at least one family-specific mutation is necessary, but not sufficient for disease development within individuals in the family.

This project utilizes a family-based whole-exome sequencing strategy (sequencing only the protein coding regions of the genome) to identify family-specific variants segregating with asthma. Families with three or more children over the age of five, at least two of whom were reported to be asthmatic, will donate blood or saliva samples to isolate DNA and be interviewed about asthma and asthma symptoms in both the parents and children. Our goal is to identify rare genetic mutations segregating with asthma and look for clusters of mutations in the same genes across the families in the study.

We have recruited and sequenced the members of 248 families. Data analysis is ongoing.

We thank you for your participation in this project. If you have any questions, please contact us at fastgen@yale.edu or 203-737-6229.

Principal Investigator: Andrew DeWan, PhD
Co-Investigators: Michael B. Bracken, PhD, Josephine Hoh, PhD

Exposure to aeroallergens and air contaminants is hypothesized to be a major factor in the exacerbation of asthma. Results of our ongoing studies suggest that nitrogen dioxide (NO₂) indoors and outdoors (associated with motor vehicle emissions) at levels well below the EPA Air Quality Standard, may be associated with respiratory symptoms in children at risk for developing asthma and with the exacerbation of asthma in asthmatic children. Our data are also suggestive of an interaction between indoor aeroallergens and NO₂ concentrations in enhancing respiratory symptoms in infants and asthmatic children. The potential impact is great since traffic volume is increasing and virtually all homes have significant dust allergen levels. We propose a prospective epidemiologic study of 1,533 children with active asthma (5 to 10 years of age), to test the hypothesis that carefully quantified NO₂ concentrations associated with vehicle traffic on state and interstate roads are associated with asthma severity. In addition, we will determine if home levels of NO₂, in the presence of common indoor dust allergens (Der p 1, Der f 1, Bla g 1, Fel d 1, Can f 1 and fungi), are associated with an increased risk of asthma severity in children sensitized to those allergens. The above hypotheses will be evaluated while adjusting for factors known or suspected to increase risk of more severe asthma, including household and school characteristics. The study population will be drawn from elementary schools in 17 Connecticut towns using a modified version of the ISAAC questionnaire to identify children with active asthma. Initial risk factors will be assessed in a home interview, and asthma severity (symptoms, frequency of ER visits, medication use) will be assessed prospectively for one year using telephone interviews administered quarterly. At the home visit, dust samples will be collected for allergen and fungi determinations and blood samples collected for antigen specific IgE determinations. Indoor and outdoor NO₂ levels will be obtained quarterly for each home. Global Information Systems in combination with road vehicle density data will be used to assess the impact of traffic on asthma severity and outdoor NO₂ concentrations at the home. Traffic-related pollution may represent an important environmental exposure for asthmatic children, for which effective interventions can be developed to reduce asthma morbidity.

Asthma and allergies are the most common chronic diseases of childhood, and their prevalence in Western countries continues to increase. Asthma and other allergic diseases are complex diseases, and environmental exposures, likely interacting with genetic risk factors, play important roles in the development of these disorders. Recent studies have shown that exposure to animals early in life may protect against asthma and allergies, and it is thought that endotoxin exposure mediates this effect. Endotoxin is comprised of soluble lipopolysaccharide (LPS) fragments of the outer membrane of gram-negative bacteria. It is postulated that endotoxin exposure may prevent the development of asthma and allergic disease depending on dose, timing, and genetics of the individual. Endotoxin is first sensed and recognized by components of the innate immune system, which then sets off a cascade of reactions, culminating in production of cytokines and co-stimulatory molecules which may be important in directing the development of the adaptive immune system. This proposal seeks to examine whether genes encoding components of the innate immune system are associated with the development of asthma and allergies, and whether endotoxin interacts with these genes in the development of these disorders. The research design will be a candidate gene case-control study, and gene-by-environment interactions will be tested. This proposal will combine resources and data from two birth cohorts: the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. In doing so, we will increase the number of cases and controls, and will be able to make use of previously collected data and specimens. Blood for genetic material is currently being collected on the two cohorts, and endotoxin will be measured from stored, frozen house dust.

Increasingly, women are asthmatic in pregnancy and their children are at higher risk. Yet little is known about perinatal risk factors that effect asthma development in young children. Environmental exposures (eg. aeroallergens, tobacco smoke, air contaminants) are known risk factors for asthma severity in children and atopic asthma is understood to relate to immune status, particularly total IgE response, but in complex and little understood ways. Several candidate genes are suggested which may increase risk of atopy and/or asthma. This proposal explores in-utero, perinatal and neonatal risk factors, e.g., poor maternal asthma management, genotype, immune status, lactation, and their interactions on infant asthma development, in a population of children whose experience in-utero was extensively monitored in 885 asthmatic and 1327 control mothers. We will follow 1680 infants to ascertain age of asthma diagnosis and its severity in the first 5-6 years of life. In-utero and perinatal risk factors have been obtained prospectively and include: obstetrical and delivery history, history of maternal asthma (measured by spirometry, symptoms, medication) and infections, prenatal medication history, maternal smoking history, job exposures and home characteristics (humidity, molds, pets, heating sources). The child’s immune status at birth will be assessed by stored cord blood total serum IgE. From cheek swabs, neonatal polymorphisms: B2 adrenergic receptor (Arg 16-Gly or Gln27-Glu); promoter region of the IL-4 gene, particularly at TT; Rsa-1 polymorphisms in the beta chain of the high affinity receptor for IgE (Fc PI- b ); tumor necrosis factor complex (LT a -Nco I, and TNF-308); CD14; IL-13; and IL-4 receptor will be assessed. Lactation, changes to housing characteristics, neo- and post-natal risk factors will be measured retrospectively by medical records and interview. Detailed characterization of maternal asthma and perinatal risk factors, and inclusion of black (10%) and Hispanic (19%) mothers, make this a unique "pregnancy cohort" for better understanding asthma onset in young children. Identification of pregnancy and neonatal risk factors for infant asthma may offer opportunities for early prevention.

Asthma is a major chronic disease in the U.S. and the most common chronic illness of childhood. The Centers for Disease Control estimate that the prevalence of asthma has increased 75% between 1980 and 1994, with disproportionate morbidity and mortality among Hispanic and African-Americans. Genetic and environmental factors are known to be important risk factors in asthma development. The interaction of specific mutations within genes with specific environmental factors (allergens, fungi, environmental tobacco smoke, etc.), however, is poorly understood despite its crucial importance in understanding the development of asthma. In this competitive renewal application, we seek to continue to follow our population of 1,002 children (549 White, 268 Hispanic, 139 African American, and 46 Other) enrolled at birth, to test the original hypothesis that carefully quantitated environmental factors (indoor allergens and environmental tobacco smoke (ETS) exposures) are associated with the incidence of asthma in children whose health status, familial history, antigen-specific IgE status, home environment, and potential confounders are carefully characterized. We have followed 103 of the children for 3 years, 508 for 2 years and 391 for one year. During the first year of life, episodes of wheeze, persistent cough, and shortness of breath were recorded for 42, 49 and 21 percent of the children. Thus far, 180 children have been reported with asthma, with higher rates for Hispanics (Puerto Rican) and African Americans. Familial history and infant mattress dust mite levels were positively associated with risk of asthma. In continuing to follow the population, we will evaluate environmental risk factors for asthma development through age 7 and assess antigen specific IgE status of the children. In this application we are proposing to expand the prospective study to explore gene-environment interactions in the risk of asthma development. We aim to investigate the respective roles of allergens, ETS and other air contaminant exposures and, initially, one of several candidate genes – a polymorphism in the promoter region of the IL-4 gene, a gene found to be important for risk of atopy and asthma development. Blood samples will be banked so that, in the future, other candidate genes may be explored. Our extensive characterization of environmental exposures and risk factors provide a unique population within which gene-environment interactions in the development of asthma and atopy can be examined and may provide information necessary for targeting and prioritizing environmental interventions toward those with genetic susceptibility.