Delineating the role of genetic factors in the development and expression of common complex disorders, and understanding gene- environment interactions has major public health significance. These genetic approaches will provide further insight into the pathophysiology of these diseases, more effective therapeutic interventions, new diagnostic methods for pre-symptomatic diagnosis that would lead to the development of strategies for early disease prevention in susceptible individuals and delineation of the interaction between genotype and response to specific treatments (pharmacogenetics). This is a renewal application for a RO1 that was originally funded for 5 years and was one of the first projects on mapping susceptibility genes for asthma that was designed to recruit asthma families and perform a genome wide screen to detect chromosomal regions with evidence for linkage. This proposal is a collaborative project with Professor Dirkje Postma at the University o f Groningen. The ascertainment and clinical characterization of the families has been performed in Groningen with funding from the Dutch Asthma Funds. The clinical and genetic analysis of the family data as well as performing a complete genome screen on the families were the goals of the original RO1.
These aims have been met and additional progress has been made in several areas. A multifaceted approach to delineate the genetic basis of asthma and associated phenotypes is being utilized in 1) the clinical ascertainment of families where both asthma and several related phenotypes are fully characterized, 2) the analytical methods where both segregation analysis is performed along with both parametric and nonparametric linkage analysis, and 3) the molecular genetic areas where a candidate gene approach for both linkage and association as well as the results of a genome screen are being utilized for mapping asthma susceptibility genes. This approach to investigate the genetics of asthma has been possible because of the unique opportunity in Groningen to study a genetically homogenous population of Dutch families identified through probands with asthma who were originally studied 25 to 35 years ago and who have been restudied along with their spouses, children and grandchildren. Therefore, we have a sample of families appropriately ascertained for segregation analysis, ideal for linkage analysis and fine mapping as well as a case-control sample for association studies (probands versus unaffected spouses) from a restricted Dutch population. The results of a genome screen in the first 140 families show several regions of interest that are novel and several that replicate the results in other reported studies. Under the original Dutch Asthma Fund grant, data was collected on 92 families which were used for our original analyses. Under the current Dutch grant, an additional 108 families are being characterized for a total of 200 families that have been ascertained with the same protocol. This homogenous Dutch population is ideal to fine map susceptibility genes for asthma and associated phenotypes using the multifaceted approach proposed in this renewal.
| Koppelman, Gerard H; Meyers, Deborah A; Howard, Timothy D et al. (2009) Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness. Am J Respir Crit Care Med 180:929-35 |
| Oostendorp, Jaap; Postma, Dirkje S; Volders, Haukeline et al. (2005) Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes. Am J Respir Crit Care Med 172:322-8 |
| Postma, Dirkje S; Meyers, Deborah A; Jongepier, Hajo et al. (2005) Genomewide screen for pulmonary function in 200 families ascertained for asthma. Am J Respir Crit Care Med 172:446-52 |
| Meyers, Deborah A; Postma, Dirkje S; Stine, O Colin et al. (2005) Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure. J Allergy Clin Immunol 115:1169-75 |
| Jongepier, H; Boezen, H M; Dijkstra, A et al. (2004) Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin Exp Allergy 34:757-60 |
| Hawkins, Gregory A; Amelung, Pamela J; Smith, Richard S et al. (2004) Identification of polymorphisms in the human glucocorticoid receptor gene (NR3C1) in a multi-racial asthma case and control screening panel. DNA Seq 15:167-73 |
| Howard, Timothy D; Postma, Dirkje S; Jongepier, Hajo et al. (2003) Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations. J Allergy Clin Immunol 112:717-22 |
| Howard, Timothy D; Meyers, Deborah A; Bleecker, Eugene R (2003) Mapping susceptibility genes for allergic diseases. Chest 123:363S-8S |
| Koppelman, G H; Jansen, D F; Schouten, J P et al. (2003) Sibling effect on atopy in children of patients with asthma. Clin Exp Allergy 33:170-5 |
| Koppelman, Gerard H; Stine, O Colin; Xu, Jianfeng et al. (2002) Genome-wide search for atopy susceptibility genes in Dutch families with asthma. J Allergy Clin Immunol 109:498-506 |
Showing the most recent 10 out of 37 publications
