Genetic Epidemiology of Asthma in Costa Rica

Asthma Clinical Trial

Official title:

Genetic Epidemiology of Asthma in Costa Rica

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00021840
• Other study ID #: 971
• Secondary ID: R37HL066289
• Status: Completed
• Phase: N/A
• First received: August 7, 2001
• Last updated: August 1, 2014
• Start date: July 2001
• Est. completion date: July 2011

Study information

• Verified date: August 2014
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

To identify genetic factors that influence the development of asthma in Hispanics.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4245
• Est. completion date: July 2011
• Est. primary completion date: July 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 6 Years and older

Eligibility

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:

1. Be at least 6 years of age

2. Have a physician diagnosis of asthma and either >/= 2 respiratory symptoms or a history of recurrent asthma attacks

3. 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)

4. Have at least 6 great-grandparents born in the Central Valley of Costa Rica

5. Have his/her parents give voluntary written consent to participate in the study

6. Give his/her assent to participate in the study.

7. 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:

1. Be adopted

2. Have a chronic respiratory disorder other than asthma (e.g., active tuberculosis, bronchiectasis). Inactive tuberculosis is not an exclusion criterion

3. 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.

Study Design

Observational Model: Family-Based, Time Perspective: Cross-Sectional

Related Conditions & MeSH terms

• Asthma
• Lung Diseases

Locations

Country	Name	City	State
Costa Rica	Hospital Nacional de Ninos	San Jose

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

Costa Rica, 

References & Publications (35)

Bunyavanich S, Soto-Quiros ME, Avila L, Laskey D, Senter JM, Celedón JC. Risk factors for allergic rhinitis in Costa Rican children with asthma. Allergy. 2010 Feb;65(2):256-63. doi: 10.1111/j.1398-9995.2009.02159.x. Epub 2009 Oct 1. — View Citation

Celedón JC, Soto-Quiros ME, Avila L, Lake SL, Liang C, Fournier E, Spesny M, Hersh CP, Sylvia JS, Hudson TJ, Verner A, Klanderman BJ, Freimer NB, Silverman EK, Weiss ST. Significant linkage to airway responsiveness on chromosome 12q24 in families of child — View Citation

Duan QL, Lasky-Su J, Himes BE, Qiu W, Litonjua AA, Damask A, Lazarus R, Klanderman B, Irvin CG, Peters SP, Hanrahan JP, Lima JJ, Martinez FD, Mauger D, Chinchilli VM, Soto-Quiros M, Avila L, Celedón JC, Lange C, Weiss ST, Tantisira KG. A genome-wide assoc — View Citation

Forno E, Celedon JC. Asthma and ethnic minorities: socioeconomic status and beyond. Curr Opin Allergy Clin Immunol. 2009 Apr;9(2):154-60. Review. — View Citation

Forno E, Fuhlbrigge A, Soto-Quirós ME, Avila L, Raby BA, Brehm J, Sylvia JM, Weiss ST, Celedón JC. Risk factors and predictive clinical scores for asthma exacerbations in childhood. Chest. 2010 Nov;138(5):1156-65. doi: 10.1378/chest.09-2426. Epub 2010 May — View Citation

Forno E, Lasky-Su J, Himes B, Howrylak J, Ramsey C, Brehm J, Klanderman B, Ziniti J, Melén E, Pershagen G, Wickman M, Martinez F, Mauger D, Sorkness C, Tantisira K, Raby BA, Weiss ST, Celedón JC. Genome-wide association study of the age of onset of childh — View Citation

Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, Wichmann HE, Meitinger T, Hunter D, Hu FB, Colditz G, Hinney A, Hebebrand J, Koberwitz K, Zhu X, Cooper R, Ardlie K, Lyon H, Hirschhorn JN, Laird NM, Lenburg ME, Lange C, Christman MF. A common — View Citation

Hersh CP, Raby BA, Soto-Quirós ME, Murphy AJ, Avila L, Lasky-Su J, Sylvia JS, Klanderman BJ, Lange C, Weiss ST, Celedón JC. Comprehensive testing of positionally cloned asthma genes in two populations. Am J Respir Crit Care Med. 2007 Nov 1;176(9):849-57. — View Citation

Hersh CP, Soto-Quirós ME, Avila L, Lake SL, Liang C, Fournier E, Spesny M, Sylvia JS, Lazarus R, Hudson T, Verner A, Klanderman BJ, Freimer NB, Silverman EK, Celedón JC. Genome-wide linkage analysis of pulmonary function in families of children with asthm — View Citation

Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, Wilk JB, Willis-Owen SA, Klanderman B, Lasky-Su J, Lazarus R, Murphy AJ, Soto-Quiros ME, Avila L, Beaty T, Mathias RA, Ruczinski I, Barnes KC, Celedón JC, Cookson WO, Gauderman WJ, — View Citation

Himes BE, Klanderman B, Ziniti J, Senter-Sylvia J, Soto-Quiros ME, Avila L, Celedón JC, Lange C, Mariani TJ, Lasky-Su J, Hersh CP, Raby BA, Silverman EK, Weiss ST, Demeo DL. Association of SERPINE2 with asthma. Chest. 2011 Sep;140(3):667-74. doi: 10.1378/ — View Citation

Himes BE, Lasky-Su J, Wu AC, Wilk JB, Hunninghake GM, Klanderman B, Murphy AJ, Lazarus R, Soto-Quiros ME, Avila L, Celedón JC, Lange C, O'Connor GT, Raby BA, Silverman EK, Weiss ST. Asthma-susceptibility variants identified using probands in case-control — View Citation

Hunninghake GM, Cho MH, Tesfaigzi Y, Soto-Quiros ME, Avila L, Lasky-Su J, Stidley C, Melén E, Söderhäll C, Hallberg J, Kull I, Kere J, Svartengren M, Pershagen G, Wickman M, Lange C, Demeo DL, Hersh CP, Klanderman BJ, Raby BA, Sparrow D, Shapiro SD, Silve — View Citation

Hunninghake GM, Lasky-Su J, Soto-Quirós ME, Avila L, Liang C, Lake SL, Hudson TJ, Spesny M, Fournier E, Sylvia JS, Freimer NB, Klanderman BJ, Raby BA, Celedón JC. Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in C — View Citation

Hunninghake GM, Soto-Quirós ME, Avila L, Kim HP, Lasky-Su J, Rafaels N, Ruczinski I, Beaty TH, Mathias RA, Barnes KC, Wilk JB, O'Connor GT, Gauderman WJ, Vora H, Baurley JW, Gilliland F, Liang C, Sylvia JS, Klanderman BJ, Sharma SS, Himes BE, Bossley CJ, — View Citation

Hunninghake GM, Soto-Quiros ME, Avila L, Ly NP, Liang C, Sylvia JS, Klanderman BJ, Silverman EK, Celedón JC. Sensitization to Ascaris lumbricoides and severity of childhood asthma in Costa Rica. J Allergy Clin Immunol. 2007 Mar;119(3):654-61. — View Citation

Hunninghake GM, Soto-Quirós ME, Avila L, Su J, Murphy A, Demeo DL, Ly NP, Liang C, Sylvia JS, Klanderman BJ, Lange C, Raby BA, Silverman EK, Celedón JC. Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood. J Allergy Clin — View Citation

Hunninghake GM, Soto-Quirós ME, Lasky-Su J, Avila L, Ly NP, Liang C, Klanderman BJ, Raby BA, Gold DR, Weiss ST, Celedón JC. Dust mite exposure modifies the effect of functional IL10 polymorphisms on allergy and asthma exacerbations. J Allergy Clin Immunol — View Citation

Lasky-Su J, Lyon HN, Emilsson V, Heid IM, Molony C, Raby BA, Lazarus R, Klanderman B, Soto-Quiros ME, Avila L, Silverman EK, Thorleifsson G, Thorsteinsdottir U, Kronenberg F, Vollmert C, Illig T, Fox CS, Levy D, Laird N, Ding X, McQueen MB, Butler J, Ardl — View Citation

Levin AM, Mathias RA, Huang L, Roth LA, Daley D, Myers RA, Himes BE, Romieu I, Yang M, Eng C, Park JE, Zoratti K, Gignoux CR, Torgerson DG, Galanter JM, Huntsman S, Nguyen EA, Becker AB, Chan-Yeung M, Kozyrskyj AL, Kwok PY, Gilliland FD, Gauderman WJ, Ble — View Citation

Ly NP, Celedón JC. Family history, environmental exposures in early life, and childhood asthma. J Allergy Clin Immunol. 2007 Aug;120(2):271-2. Review. — View Citation

Ly NP, Soto-Quirós ME, Avila L, Hunninghake GM, Raby BA, Laskey D, Sylvia JS, Celedón JC. Paternal asthma, mold exposure, and increased airway responsiveness among children with asthma in Costa Rica. Chest. 2008 Jan;133(1):107-14. Epub 2007 Nov 7. — View Citation

Lyon HN, Emilsson V, Hinney A, Heid IM, Lasky-Su J, Zhu X, Thorleifsson G, Gunnarsdottir S, Walters GB, Thorsteinsdottir U, Kong A, Gulcher J, Nguyen TT, Scherag A, Pfeufer A, Meitinger T, Brönner G, Rief W, Soto-Quiros ME, Avila L, Klanderman B, Raby BA, — View Citation

Melén E, Granell R, Kogevinas M, Strachan D, Gonzalez JR, Wjst M, Jarvis D, Ege M, Braun-Fahrländer C, Genuneit J, Horak E, Bouzigon E, Demenais F, Kauffmann F, Siroux V, Michel S, von Berg A, Heinzmann A, Kabesch M, Probst-Hensch NM, Curjuric I, Imboden — View Citation

Murphy A, Tantisira KG, Soto-Quirós ME, Avila L, Klanderman BJ, Lake S, Weiss ST, Celedón JC. PRKCA: a positional candidate gene for body mass index and asthma. Am J Hum Genet. 2009 Jul;85(1):87-96. doi: 10.1016/j.ajhg.2009.06.011. Epub 2009 Jul 2. Erratu — View Citation

Myers RA, Himes BE, Gignoux CR, Yang JJ, Gauderman WJ, Rebordosa C, Xie J, Torgerson DG, Levin AM, Baurley J, Graves PE, Mathias RA, Romieu I, Roth LA, Conti D, Avila L, Eng C, Vora H, LeNoir MA, Soto-Quiros M, Liu J, Celedón JC, Galanter JM, Farber HJ, K — View Citation

Pistiner M, Gold DR, Abdulkerim H, Hoffman E, Celedón JC. Birth by cesarean section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy. J Allergy Clin Immunol. 2008 Aug;122(2):274-9. doi: 10.1016/j.jaci.2008.05. — View Citation

Raby BA, Soto-Quiros ME, Avila L, Lake SL, Murphy A, Liang C, Fournier E, Spesny M, Sylvia JS, Verner A, Hudson TJ, Klanderman BJ, Freimer NB, Silverman EK, Celedón JC. Sex-specific linkage to total serum immunoglobulin E in families of children with asth — View Citation

Sabatti C, Service S, Freimer N. False discovery rate in linkage and association genome screens for complex disorders. Genetics. 2003 Jun;164(2):829-33. — View Citation

Scirica CV, Celedón JC. Genetics of asthma: potential implications for reducing asthma disparities. Chest. 2007 Nov;132(5 Suppl):770S-781S. Review. — View Citation

Sharma S, Murphy AJ, Soto-Quiros ME, Avila L, Klanderman BJ, Sylvia JS, Celedón JC, Raby BA, Weiss ST. Association of VEGF polymorphisms with childhood asthma, lung function and airway responsiveness. Eur Respir J. 2009 Jun;33(6):1287-94. doi: 10.1183/090 — View Citation

Sharma S, Raby BA, Hunninghake GM, Soto-Quirós M, Avila L, Murphy AJ, Lasky-Su J, Klanderman BJ, Sylvia JS, Weiss ST, Celedón JC. Variants in TGFB1, dust mite exposure, and disease severity in children with asthma. Am J Respir Crit Care Med. 2009 Mar 1;17 — View Citation

Sharma S, Tantisira K, Carey V, Murphy AJ, Lasky-Su J, Celedón JC, Lazarus R, Klanderman B, Rogers A, Soto-Quirós M, Avila L, Mariani T, Gaedigk R, Leeder S, Torday J, Warburton D, Raby B, Weiss ST. A role for Wnt signaling genes in the pathogenesis of im — View Citation

Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, Himes BE, Levin AM, Mathias RA, Hancock DB, Baurley JW, Eng C, Stern DA, Celedón JC, Rafaels N, Capurso D, Conti DV, Roth LA, Soto-Quiros M, Togias A, Li X, Myers RA, Romieu I, Van — View Citation

Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Larivière M, Moussette S, Grundberg E, Kwan T, Ouimet M, Ge B, Hoberman R, Swiatek M, Dias J, Lam KC, Koka V, Harmsen E, Soto-Quiros M, Avila L, Celedón JC, Weiss ST, Dewar K, Sinnett D, Laprise C, Raby B — View Citation

* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Asthma diagnosis and asthma morbidity		Baseline/entry to study	No
Secondary	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	No