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, L3 6
Sun, L5
Berthiaume, Y1
Tsui, LC2 6
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
2011 Impact Factor: 13.069
2011 SCImago Journal Rankings: 2.512
DOIhttp://dx.doi.org/10.1172/JCI33754
ISI Accession Number IDWOS:000253646400028
PubMed Central IDPMC2248329
ReferencesReferences in Scopus
DC Field
Value
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.isiWOS:000253646400028
dc.identifier.issn0021-9738
2011 Impact Factor: 13.069
2011 SCImago Journal Rankings: 2.512
dc.identifier.issue3
dc.identifier.openurl
dc.identifier.pmcidPMC2248329
dc.identifier.pmid18292811
dc.identifier.scopuseid_2-s2.0-40549083327
dc.identifier.spage1040
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
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, Toronto