Genetic Epidemiology of Asthma in Costa Rica

Study Overview
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Brief Summary
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To identify genetic factors that influence the development of asthma in Hispanics.

Detailed Description
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BACKGROUND: Asthma is a major public health problem in the United States, with particularly high prevalence rates among some Hispanic groups. Genetic linkage studies of this disease are of potentially great utility for the identification of those at risk, the search for new pharmaceutical treatments, and designing interventions to prevent development of asthma. Study power is greatly enhanced if a relatively isolated, homogeneous population with a significant prevalence of asthma can be identified. Such a population does not exist among Hispanics in the United States but is available in the Central Valley of Costa Rica. DESIGN NARRATIVE: The study concentrates on a genetically isolated Hispanic population with high asthma prevalence living in the Central Valley of Costa Rica. A genome screen will be conducted on large pedigrees multiplex for asthma and linkage analysis performed for seven intermediate phenotypes related to asthma including airway responsiveness; FEV1; bronchodilator responsiveness; skin test reactivity to common aeroallergens; serum total and allergen-specific IgE; and peripheral blood eosinophil count. A genome screen will also be conducted in the parent-child trios, and ancestral haplotypes will be reconstructed to identify regions influencing asthma-associated phenotypes. Within candidate regions demonstrating both linkage in extended pedigrees to asthma and/or asthma-related phenotypes and significant linkage disequilibrium within the unrelated asthmatic subjects, fine mapping will be performed by testing for genetic association to single nucleotide polymorphisms within positional candidate genes.

Official Title
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Genetic Epidemiology of Asthma in Costa Rica

Conditions
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Asthma, Lung Diseases

Participation Criteria
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Eligibility Criteria
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Selection and Extension of Family Pedigrees Probands will be selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. At least 15 families, each having at least two siblings and no more than one parent with a physician diagnosis of asthma will be ascertained and enrolled into this study in Costa Rica. All available first- and second-degree relatives of the proband will be enrolled, including affected and unaffected individuals. Probands will be recruited from 72 asthmatic children ages 6-12 yr that participated in phase II of the International Study of Asthma and Allergies in Childhood (ISAAC). The Principal Investigator for this study in Costa Rica, Dr. Manuel Soto-Quiros, has been collaborating with us for over a year on a pilot study of the genetics of asthma in Costa Rica. Informed consent for this study was approved by the IRB of the Hospital Nacional de Ninos (San Jose, Costa Rica) and the Costa Rican Ministry of Health, and approval was obtained from the Institutional Review Board of the Brigham and Women's Hospital for genotyping and data analysis. The parents of these children provided information on their respiratory health status and that of their children. Lineages for these 72 children (the probands) were traced back at least three generations. All of these children have at least 6 great-grandparents from Central Valley origins, and are therefore descended primarily from the original founders of the population of the Central Valley of Costa Rica. After determining eligibility, Dr. Soto-Quiros will contact the parents of eligible children. If we are unable to recruit 15 such families from the 72 families participating in Phase II of ISAAC, we will apply the same criteria for selection of the family pedigrees to 315 parent-child trios enrolled in the proposed study. We will, however, exclude trios that are selected for pedigree extension from any of the analyses planned on parent-child trios recruited for the present study. Parents of eligible children will be contacted by Dr. Soto-Quiros by mail or by phone, according to their preference. Once an asthmatic child's family is selected for extension, we will give copies of a brief study description to the proband's parents, so that they can keep a copy for themselves and distribute the others to interested relatives. We will then ask the proband's parents to ask their relatives for permission to be contacted regarding the study. Relatives that have given us permission to be contacted through the proband's parents will be called by telephone to explain the study and to set up interviews. Parent-Child Trios Probands will be selected using the same criteria outlined above. 1,200 asthmatic children and their parents (3,600 individuals) will be ascertained and enrolled in this study in the Central Valley of Costa Rica. Probands will be recruited from approximately 3,500 schoolchildren ages 6-12 yr from the Central Valley of Costa Rica. A short screening questionnaire will be administered to the parents of these children to obtain information about the child's respiratory health status and the last names of both of his/her parents. The parents will be instructed to have their child take the completed questionnaire back to school in a sealed envelope. Based on this information, we anticipate selecting 800 children with a physician diagnosis of asthma; either >/= 2 respiratory symptoms or history of recurrent asthma attacks; and a high probability of having >/= 6 great-grandparents from Central Valley origins, as determined by our genealogist. Once an asthmatic child's family is selected, we will ask permission of the parents to conduct methacholine challenge testing on the index children to determine whether or not they are true asthmatics. Inclusion Criteria A family will be eligible for inclusion in this study only if the asthmatic proband in that family meets all of the following criteria. Each proband must: Be at least 6 years of age Have a physician diagnosis of asthma and either >/= 2 respiratory symptoms or a history of recurrent asthma attacks Have either airway hyperresponsiveness to methacholine (PD20 </= 16 mg/ml) or (if the FEV1 is </= 65% of predicted) a significant bronchodilator response (an increase of at least 12% from baseline FEV1) Have at least 6 great-grandparents born in the Central Valley of Costa Rica Have his/her parents give voluntary written consent to participate in the study Give his/her assent to participate in the study. Have at least 2 siblings with physician-diagnosed asthma and no more than one parent with a physician diagnosis of asthma All first- and second-degree relatives of the proband, affected and unaffected will be enrolled in the study of 15 large, multigenerational family pedigrees if available and willing to participate. The natural mother and father of the proband will be enrolled in the study of 600 parent-child trios if available and willing to participate. Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply. Each subject must not: Be adopted Have a chronic respiratory disorder other than asthma (e.g., active tuberculosis, bronchiectasis). Inactive tuberculosis is not an exclusion criterion For the study of large, multigenerational pedigrees only: Have a familial relationship to any of the remaining fourteen (14) families over the last four generations. Subject reconsideration for Inclusion Subjects fulfilling the following exclusion criteria below may be eligible for inclusion in the study at a later date provided that the study physician does not feel that their participation will adversely influence the results of the study. 1. Subjects who have taken antibiotics for respiratory disease within one month or have had respiratory infection within 6 weeks of the visit.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Homogen Hispanic pop/Cent Valley CRA<br>Homogeneous Hispanic population from the Central Valley of Costa Rica | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma diagnosis and asthma morbidity |  | Baseline/entry to study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung function measures | Includes lung function measures via spirometry, pre-/post-bronchodilator (BD) results, methacholine challenge results, specific IgE measurements, exposure measurements (e.g., house dust samples/allergens, endotoxin levels in house dust, questionnaire-based exposures to smoking, pets, siblings, etc.) | 11 years |