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

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 (TNF alpha), transforming growth factor beta 1 (TGF beta 1) or mannose-binding lectin (MBL2)) differed among patients with cystic fibrosis grouped according to age and survival status. Methods: Genotypes of four variants (TNF alpha-238, TNF alpha-308, TGF beta 1-509 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 < 17 years; mean age 30.8 years) and 38 nonsurviving 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 TNF alpha-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 ( TNF alpha-238 G/G vs G/A; p = 0.0015 and MBL2: A/A vs O/O; p = 0.009). The hazard ratio for TNF alpha-238 G/ G vs G/A was 0.25 (95% Cl 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: TNF alpha-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival of cystic fibrosis.