Research Project

Summary

Canada is a world leader in research on cystic fibrosis (CF). Project leaders Dr. Peter Durie, a pediatrician and senior scientist, and Julian Zielenski, a geneticist at the Hospital for Sick Children's Research Institute, plan to build on this research strength by investigating the genetics of other diseases with similar phenotypes – observable physical characteristics, which may be genetically determined.

The research team is applying knowledge about the genetic factors (so-called modifier genes) that influence the severity of CF to other, clinically similar diseases. These conditions include a single-gene disorder affecting the liver (a1-antitrypsin deficiency) and multifactorial conditions such as pancreatitis due to alcohol abuse and chronic obstructive pulmonary disease resulting from smoking. The project is analysing mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR), certain modifier genes that influence the severity of disease in patients with CF, and blood-circulating proteins, in order to identify biomarkers that can help predict severity and progression of disease. The team will develop diagnostic and prognostic tests, and genetic test-based risk identification could lead to behaviour modification and disease prevention among those at risk for the diseases.

Enormous human suffering and prohibitive healthcare costs result from alcohol abuse and tobacco smoking. This project should yield results applicable around the world - for example, in development of genetic tests of disease susceptibility that will assist future research and in the search for preventive strategies to modify behaviour in high-risk populations. This in turn should reduce morbidity and mortality and make healthcare more efficient. Valuable components of the project are ethical issues relating to genomics research, as well as industrial, economic, and social benefits.

This project includes integrated GE³LS research on the perspectives of study participants and researchers with respect to the reporting of genetic research results. For more information, click here.

Significant Outcomes to Date

• The project has developed the Cystic Fibrosis Mutation Database, which contains mutations associated with CF, as well as phenotypic data associated with the genotypes.
• The project team has identified the SERPINA1 Z allele, a variant of alpha-1-antitrypsin, as a marker for the development of severe liver disease in cystic fibrosis patients. See the JAMA publication below for further details.
• The project has identified mutations in the ADIPOR2 gene on chromosome 12, the gene that encodes one of the two adiponectin receptors, which are associated with meconium ileus susceptibility. See the Human Genetics publication listed below for further details.

High-Impact Publications

Bartlett JR, et al. 2009.  Genetic modifiers of liver disease in cystic fibrosis.  JAMA 302: 1076-1083.

Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, Colombo JL, Debray D, Fernandez A, Lacaille F, Macek M Jr, Rowland M, Salvatore F, Taylor CJ, Wainwright C, Wilschanski M, Zemková D, Hannah WB, Phillips MJ, Corey M, Zielenski J, Dorfman R, Wang Y, Zou F, Silverman LM, Drumm ML, Wright FA, Lange EM, Durie PR, Knowles MR; Gene Modifier Study Group. 2009. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 302(10):1076-83.

Dorfman R, Li W, Sun L, Lin F, Wang Y, Sandford A, Paré PD, McKay K, Kayserova H, Piskackova T, Macek M, Czerska K, Sands D, Tiddens H, Margarit S, Repetto G, Sontag MK, Accurso FJ, Blackman S, Cutting GR, Tsui LC, Corey M, Durie P, Zielenski J, Strug LJ. 2009. Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results. Hum. Genet. [Epub ahead of print].

Dorfman R, Sandford A, Huang B, Frangolias D, Wang Y, Sang R, Pereira L, Sun L, Berthiaume Y, Tsui LC, Paré PD, Durie P, Corey M, and Zielenski J. 2008. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J Clin Invest. 118(3):839-41.

Aznarez, I., Barash, Y., Shai, O., He, D., Zielenski , J., Tsui, L-C., Parkinson, J., Frey, B., Rommens, J., and Blencowe, B.  2008. A systematic analysis of intronic sequences downstream of 5’ splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation.  Genome Res. 18(8): 1247-58

Aznarez I, Zielenski J, Rommens JM, Blencowe BJ, and Tsui LC.  2007. Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X. J Med Genet. 44: 341-6.