Asthma is a common clinical disorder characterized by reversible obstruction of the bronchial airways which is an increasingly serious cause of morbidity and mortality in the general U.S. population. The prevalence of asthma in the population is estimated to range from 3% - 5%, with children between the ages of 3 - 11 years are at greatest risk. Both sexes and all racial groups equally affected . The overall objective of this application in response to RFA-NIH-92-HL-04-L is to initiate interdisciplinary molecular genetic studies of asthma in twelve large, extensively studied pedigrees. We propose to further characterize the clinical features and parameters associated with asthma in our previously identified pedigrees, collect and process blood samples from family members, review and retest each member using NHLBI approved protocols for diagnosis of asthma and associated findings , collect environmental and occupational history data, establish immortalized cell lines, genotype informative pedigree members using repetitive sequence (GT)n DNA polymorphisms, and perform statistical genetic analyses of the data. We have identified 12 pedigrees suitable for gene mapping, each of which has been followed by us for over 25 years. Many of these pedigrees have been highly characterized with respect to selected genetic markers, skin testing to common aeroallergens, IgE levels (total and specific), physical examination, and pulmonary function. Most individuals in these pedigrees have been followed on a yearly basis for over 20 years. We have already successfully contacted multiple individuals in each of the twelve ascertained pedigrees and have obtained their consent to participate in this study. The presence of a genetic component to the susceptibility of asthma has been suggested from evidence of population, twin, and family studies. Based upon the accumulated data, multiple cell types and numerous cellular control mechanisms influence the development of asthma and its response to treatment. Both complex phenotypes (asthma) and intermediate phenotypes (atopy, specific immune responses, serum IgE levels, mediator release, bronchial hyperreactivity) will used to investigate genetic susceptibility of the observed clinical syndrome of asthma. Our central hypothesis is that asthma is heterogeneous at both the phenotypic and genetic level; yet, in our informative pedigrees, the application of the linkage strategy, using (GT)n repeat polymorphisms and robust sib pair method of analysis, will allow us to identify potential loci that have single or multiple effects on asthma and its component phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL049609-01
Application #
3553569
Study Section
Special Emphasis Panel (ZHL1-CCT-P (S1))
Project Start
1992-09-30
Project End
1997-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Blumenthal, Malcolm N; Langefeld, Carl D; Barnes, Kathleen C et al. (2006) A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity. J Allergy Clin Immunol 117:79-85
Blumenthal, Malcolm N; Rosenberg, Andreas (2004) Definition of an allergen (immunobiology). Clin Allergy Immunol 18:37-50
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Blumenthal, Malcolm N; Langefeld, Carl D; Beaty, Terri H et al. (2004) A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma. Hum Genet 114:157-64
Hsu, Fang-Chi; Liang, Kung-Yee; Beaty, Terri H (2003) Multipoint linkage disequilibrium mapping approach: incorporating evidence of linkage and linkage disequilibrium from unlinked region. Genet Epidemiol 25:1-13
Colilla, Susan; Nicolae, Dan; Pluzhnikov, Anna et al. (2003) Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol 111:840-6
Blumenthal, Malcolm M (2002) What we know about the genetics of asthma at the beginning of the 21st century. Clin Rev Allergy Immunol 22:11-31
Lester, L A; Rich, S S; Blumenthal, M N et al. (2001) Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma. J Allergy Clin Immunol 108:357-62

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