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Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection

Abstract

Cystic fibrosis (CF) is one of the most common life-shortening genetic disorders, and the CF transmembrane conductance regulator (CFTR) is the major causal gene. However, a substantial clinical variability among patients with identical CFTR genotypes suggests the presence of modifier genes. We tested the effect of four genes involved in Pseudomonas aeruginosa infection. Analysis of a primary cohort detected eight candidate polymorphisms that were genotyped in the secondary cohort of 1579 patients; lung function and age at first infection with P. aeruginosa were considered as the phenotypes. Both additive and codominant models were considered, adjusting for confounding variables but not for multiple comparisons. In the secondary cohort, heme oxygenase-1 (HMOX1) rs2071749 had the most significant effect on lung function in the pediatric group (P=0.01; Pcorrected=0.03), and complement factor 3 (C3) rs11569393 and HMOX1 rs2071746 in the adult groups (P=0.03 for both variants; Pcorrected=0.16, 0.09). No polymorphism of complement factor B (CFB) or toll-like receptor 4 (TLR4) had a significant modifying effect on lung function in either group. We have identified two genes that showed nominal association with disease severity among CF patients. However, because of the multiple comparisons made, further studies are required to confirm the interaction between these modifying genes and CFTR.

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Acknowledgements

We thank the CF Directors for their significant contribution and Clinic Coordinators at each CF center that enrolled subjects and ascertained phenotype data and DNA as part of the Canadian Cystic Fibrosis Genetic Modifier Study. We also thank all CF patients and their families. This work was supported by the Genome Canada through the Ontario Genomics Institute (2004-OGI-3-05 to PRD) and the Canadian Cystic Fibrosis Foundation (operating grants to PRD and AJS). DD is currently holding a Canada Research Chair on the Genetic Epidemiology of Complex Diseases and a Michael Smith Foundation for Health Research Career Scholar Award. AJS is the recipient of a Canada Research Chair in genetics and a Michael Smith Foundation for Health Research Senior Scholar Award.

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Correspondence to A J Sandford.

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Park, J., Yung, R., Stefanowicz, D. et al. Cystic fibrosis modifier genes related to Pseudomonas aeruginosa infection. Genes Immun 12, 370–377 (2011). https://doi.org/10.1038/gene.2011.5

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