Cystic fibrosis (CF) is a highly variable but inevitably fatal single gene disorder. Several lines of evidence suggest that genetic background contributes to the variability of CF phenotypes. We propose to develop CF as a model for the identification of modifier genes by capitalizing on the availability of a large motivated population of affected twins and siblings. The study has four aims: 1. To identify heritable CF phenotypes by twin study. Intrapair and interpair variance will be determined for selected CF phenotypes, and interclass correlations (MZ vs DZ) will be performed to identify CF phenotypes with a substantial heritable component. 2. To determine the contribution of genetic and other factors to the variability of CF phenotypes by analysis of affected sibs. Variance component methods will be used to evaluate the CF phenotypes that appear to be heritable based upon other studies or the results of aim 1. 3. To identify biologic phenotypes that correlate with heritable CF phenotypes by clinical study of twins and sibs. Multivariate analysis will be used to find biologic phenotypes associated with CF phenotypes. 4. To identify modifier genes and loci responsible for heritable CF phenotypes by linkage approaches. Identity by descent and transmission disequilibrium methods will be used to test linkage between candidate genes/loci and heritable CF phenotypes. To identify novel loci, genome-wide scans will be performed upon sib pairs selected for extreme concordance or discordance for heritable traits.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068927-02
Application #
6527976
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Program Officer
Banks-Schlegel, Susan P
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$1,006,851
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Collaco, Joseph M; Raraigh, Karen S; Appel, Lawrence J et al. (2016) Respiratory pathogens mediate the association between lung function and temperature in cystic fibrosis. J Cyst Fibros 15:794-801
Corvol, Harriet; Blackman, Scott M; Boƫlle, Pierre-Yves et al. (2015) Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat Commun 6:8382
Park, Jeenah; Sharma, Neeraj; Cutting, Garry R (2014) Melanocortin 3 receptor has a 5' exon that directs translation of apically localized protein from the second in-frame ATG. Mol Endocrinol 28:1547-57
Morrow, Christopher B; Raraigh, Karen S; Green, Deanna M et al. (2014) Cat and dog exposure and respiratory morbidities in cystic fibrosis. J Pediatr 165:830-5.e2
Collaco, Joseph M; Morrow, Christopher B; Green, Deanna M et al. (2013) Environmental allergies and respiratory morbidities in cystic fibrosis. Pediatr Pulmonol 48:857-64
Blackman, Scott M; Commander, Clayton W; Watson, Christopher et al. (2013) Genetic modifiers of cystic fibrosis-related diabetes. Diabetes 62:3627-35
Sun, Lei; Rommens, Johanna M; Corvol, Harriet et al. (2012) Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet 44:562-9
Green, Deanna M; Collaco, J Michael; McDougal, Kathryn E et al. (2012) Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis. J Pediatr 161:290-5.e1
Bradley, Gia M; Blackman, Scott M; Watson, Christopher P et al. (2012) Genetic modifiers of nutritional status in cystic fibrosis. Am J Clin Nutr 96:1299-308
Henderson, Lindsay B; Doshi, Vishal K; Blackman, Scott M et al. (2012) Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis. PLoS Genet 8:e1002580

Showing the most recent 10 out of 41 publications