title: Variants in mannose-binding lectin and tumour necrosis factor alpha affect survival in cystic fibrosis.
abstract: BACKGROUND
  Patients with cystic fibrosis with the same mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene differ widely in survival suggesting other factors have a substantial role in mortality.
  
  
  OBJECTIVE
  To determine if the genotype distribution of variants in three putative cystic fibrosis modifier genes (tumour necrosis factor alpha (TNFalpha), transforming growth factor beta1 (TGFbeta1) or mannose-binding lectin (MBL2)) differed among patients with cystic fibrosis grouped according to age and survival status.
  
  
  METHODS
  Genotypes of four variants (TNFalpha-238, TNFalpha-308, TGFbeta1-509 and MBL2 O) were determined in three groups of Caucasians from a single medical centre: 101 children with cystic fibrosis (aged <17 years; mean age 9.4 years), 115 adults with cystic fibrosis (aged > or =17 years; mean age 30.8 years) and 38 non-surviving adults with cystic fibrosis (21 deceased and 17 lung transplant after 17 years of age). Genotypes of 127 healthy Caucasians in the same geographical region were used as controls. Kaplan-Meier and Cox hazard regression were used to evaluate the genotype effect on cumulative survival.
  
  
  RESULTS
  Genotype frequencies among adults and children with cystic fibrosis differed for TNFalpha-238 (G/G vs G/A; p = 0.022) and MBL2 (A/A vs O/O; p = 0.016). When adults with cystic fibrosis were compared to non-surviving adults with cystic fibrosis, genotype frequencies of both genes differed (TNFalpha-238G/G vs G/A; p = 0.0015 and MBL2: A/A vs O/O; p = 0.009). The hazard ratio for TNFalpha-238G/G vs G/A was 0.25 (95% CI 0.06 to 1.0, p = 0.04) and for MBL2 O/O vs A/A or A/O was 2.5 (95% CI 1.3 to 4.9, p = 0.007).
  
  
  CONCLUSIONS
  TNFalpha-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival of cystic fibrosis.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, Maryland, USA.
authors.forename: Kitti
authors.initials: K
authors.lastname: Buranawuti
authors.forename: Michael P
authors.initials: MP
authors.lastname: Boyle
authors.forename: Suzanne
authors.initials: S
authors.lastname: Cheng
authors.forename: Lori L
authors.initials: LL
authors.lastname: Steiner
authors.forename: Kathryn
authors.initials: K
authors.lastname: McDougal
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Christian
authors.initials: C
authors.lastname: Merlo
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Zeitlin
authors.forename: Beryl J
authors.initials: BJ
authors.lastname: Rosenstein
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mogayzel
authors.forename: Xinjing
authors.initials: X
authors.lastname: Wang
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003550:Cystic Fibrosis / Q000235:genetics* / Q000401:mortality; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics*; D010641:Phenotype; D016016:Proportional Hazards Models; D016019:Survival Analysis; D017741:Survivors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin; D014409:Tumor Necrosis Factor-alpha