Child Health Evaluative science Program

Toronto, Canada

Child Health Evaluative science Program

Toronto, Canada
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Blohmke C.J.,BC Childrens Hospital | Park J.,University of British Columbia | Hirschfeld A.F.,BC Childrens Hospital | Victor R.E.,BC Childrens Hospital | And 10 more authors.
Journal of Immunology | Year: 2010

New treatments are needed to improve the health of people with cystic fibrosis (CF). Reducing lung-damaging inflammation is likely to be beneficial, but specific anti-inflammatory targets have not been identified. By combining cellular immunology with a populationbased genetic modifier study, we examined TLR5 as an anti-inflammatory target and modifier gene in CF. Using two pairs of human CF and control airway epithelial cells, we demonstrated that the TLR5-flagellin interaction is a major mediator of inflammation following exposure to Pseudomonas aeruginosa. To validate TLR5 as an anti-inflammatory target, we analyzed the disease modifying effects of the TLR5 c.1174C> T single nucleotide polymorphism (rs5744168) in a large cohort of CF patients (n = 2219). rs5744168 encodes a premature stop codon and the T allele is associated with a 45.5-76.3% reduction in flagellin responsiveness (p < 0.0001). To test the hypothesis that reduced TLR5 responsiveness would be associated with improved health in CF patients, we examined the relationship between rs5744168 and two clinical phenotypes: lung function and body weight. Adults with CF carrying the TLR5 premature stop codon (CT or TT genotype) had a higher body mass index than did CF patients homozygous for the fully functional allele (CC genotype) (p = 0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Although follow-up studies are needed to confirm the impact of TLR5 on nutritional status, this translational research provides evidence that genetic variation in TLR5 resulting in reduced flagellin responsiveness is associated with improved health indicators in adults with CF. Copyright © 2010 by The American Association of Immunologists, Inc.

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