Genetic Modifiers of Cystic Fibrosis: Sibling Study

The purpose of this study is to identify modifier genes in cystic fibrosis (CF).

Study Overview

• Status: Completed
• Conditions: Lung Diseases; Cystic Fibrosis

Detailed Description

BACKGROUND:

CF is a highly variable but inevitably fatal single gene disorder. Several lines of evidence suggest that genetic background contributes to the variability of cystic fibrosis phenotypes. The study will 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 is in response to a Request for Applications titled "Genetic Modifiers of Single Gene Defect Diseases" released in August 2000 and co-sponsored by the National Institute of Diabetes, Digestive, and Kidney Diseases.

DESIGN NARRATIVE:

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 (monozygotic versus dizygotic) 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.

• Study Type: Observational
• Enrollment (Actual): 3459

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Siblings with cystic fibrosis

Description

Inclusion Criteria:

• Diagnosis of CF

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Variation among genes in siblings with cystic fibrosis as assessed by DNA	Single collection

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Garry Cutting, Johns Hopkins University

Publications and helpful links

General Publications

• McWilliams R, Hoover-Fong J, Hamosh A, Beck S, Beaty T, Cutting G. Problematic variation in local institutional review of a multicenter genetic epidemiology study. JAMA. 2003 Jul 16;290(3):360-6. doi: 10.1001/jama.290.3.360.
• Groman JD, Hefferon TW, Casals T, Bassas L, Estivill X, Des Georges M, Guittard C, Koudova M, Fallin MD, Nemeth K, Fekete G, Kadasi L, Friedman K, Schwarz M, Bombieri C, Pignatti PF, Kanavakis E, Tzetis M, Schwartz M, Novelli G, D'Apice MR, Sobczynska-Tomaszewska A, Bal J, Stuhrmann M, Macek M Jr, Claustres M, Cutting GR. Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet. 2004 Jan;74(1):176-9. doi: 10.1086/381001. Epub 2003 Dec 18.
• Boyle MP. Nonclassic cystic fibrosis and CFTR-related diseases. Curr Opin Pulm Med. 2003 Nov;9(6):498-503. doi: 10.1097/00063198-200311000-00009.
• Hefferon TW, Groman JD, Yurk CE, Cutting GR. A variable dinucleotide repeat in the CFTR gene contributes to phenotype diversity by forming RNA secondary structures that alter splicing. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3504-9. doi: 10.1073/pnas.0400182101. Epub 2004 Mar 1.

Study record dates

Study Major Dates

• Study Start: September 1, 2001
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: May 20, 2002
• First Submitted That Met QC Criteria: May 20, 2002
• First Posted (Estimate): May 21, 2002

Study Record Updates

• Last Update Posted (Estimate): August 31, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Lung Diseases; Cystic Fibrosis
• Other Study ID Numbers: 1178; R01HL068927 (U.S. NIH Grant/Contract)