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Article: Complex two-gene modulation of lung disease severity in children with cystic fibrosis
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TitleComplex two-gene modulation of lung disease severity in children with cystic fibrosis
 
AuthorsDorfman, R6
Sandford, A4
Taylor, C6
Huang, B6
Frangolias, D4
Wang, Y6
Sang, R6
Pereira, L6 3
Sun, L5
Berthiaume, Y1
Tsui, LC6 2
Paré, PD4
Durie, P6
Corey, M6
Zielenski, J6
 
Issue Date2008
 
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
CitationJournal Of Clinical Investigation, 2008, v. 118 n. 3, p. 1040-1049 [How to Cite?]
DOI: http://dx.doi.org/10.1172/JCI33754
 
AbstractAlthough cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-β1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
 
DescriptionComment in J Clin Invest. 2008 Mar;118(3):839-841
 
ISSN0021-9738
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
 
DOIhttp://dx.doi.org/10.1172/JCI33754
 
PubMed Central IDPMC2248329
 
ISI Accession Number IDWOS:000253646400028
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorDorfman, R
 
dc.contributor.authorSandford, A
 
dc.contributor.authorTaylor, C
 
dc.contributor.authorHuang, B
 
dc.contributor.authorFrangolias, D
 
dc.contributor.authorWang, Y
 
dc.contributor.authorSang, R
 
dc.contributor.authorPereira, L
 
dc.contributor.authorSun, L
 
dc.contributor.authorBerthiaume, Y
 
dc.contributor.authorTsui, LC
 
dc.contributor.authorParé, PD
 
dc.contributor.authorDurie, P
 
dc.contributor.authorCorey, M
 
dc.contributor.authorZielenski, J
 
dc.date.accessioned2011-10-31T06:32:22Z
 
dc.date.available2011-10-31T06:32:22Z
 
dc.date.issued2008
 
dc.description.abstractAlthough cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-β1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
 
dc.description.naturepublished_or_final_version
 
dc.descriptionComment in J Clin Invest. 2008 Mar;118(3):839-841
 
dc.identifier.citationJournal Of Clinical Investigation, 2008, v. 118 n. 3, p. 1040-1049 [How to Cite?]
DOI: http://dx.doi.org/10.1172/JCI33754
 
dc.identifier.doihttp://dx.doi.org/10.1172/JCI33754
 
dc.identifier.epage1049
 
dc.identifier.f10001104979
 
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dc.identifier.f10001104979
 
dc.identifier.isiWOS:000253646400028
 
dc.identifier.issn0021-9738
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
 
dc.identifier.issue3
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2248329
 
dc.identifier.pmid18292811
 
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dc.identifier.urihttp://hdl.handle.net/10722/143107
 
dc.identifier.volume118
 
dc.languageeng
 
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Clinical Investigation
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshCystic Fibrosis - genetics - physiopathology
 
dc.subject.meshLung - physiopathology
 
dc.subject.meshMannose-Binding Lectin - blood - genetics
 
dc.subject.meshPseudomonas Infections - etiology
 
dc.subject.meshTransforming Growth Factor beta1 - genetics
 
dc.titleComplex two-gene modulation of lung disease severity in children with cystic fibrosis
 
dc.typeArticle
 
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Author Affiliations
  1. Centre Hospitalier de L'Universite de Montreal
  2. The University of Hong Kong
  3. Universidade Federal do Parana
  4. The University of British Columbia
  5. University of Toronto
  6. Hospital for Sick Children University of Toronto