Variants in mannose-binding lectin and tumour necrosis factor affect survival in cystic fibrosis

Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, United States
Journal of Medical Genetics (Impact Factor: 6.34). 03/2007; 44(3):209-14. DOI: 10.1136/jmg.2006.046318
Source: PubMed


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.
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.
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.
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).
TNFalpha-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival of cystic fibrosis.

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Available from: Kitti Buranawuti
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    • "SLC9A3 521096 C >T 4957061 Age of first P. aeruginosa infection 0.02 1,004 Decline of lung function (FEV 1 ) 0.05 752 (Dorfman et al., 2011) SNAP23 c.267-9T > C 9302112 FEF 50 0.0088 95 (Gisler et al., 2012) Functional residual capacity 0.011 Volume of trapped gas 0.0043 TGFB1 codon 10 C29T 1800470 Age at which FEV 1 < 50% Age at which FVC < 70% <0.02 <0.005 171 (Arkwright et al., 2000) * 261 (Arkwright et al., 2003) 118 (Brazova et al., 2006) 1,978 (Wright et al., 2011) codon 25 G74C 1800471 Age at which FEV 1 < 50% Age at which FVC < 70% NS NS 808 (Drumm et al., 2005) * C-509T 1800469 Impairment of lung function (FEV 1 ) 0.006 808 (Drumm et al., 2005) 498 (Drumm et al., 2005) 254 (Buranawuti et al., 2007) 329 (Corvol et al., 2008) 105 (Faria et al., 2009) 472 (Bremer et al., 2008) TLR4 D299G 4986790 Mean FEV 1 % pred 0.55 100 (Urquhart et al., 2006 "
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