ORIGINAL ARTICLE

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

Kitti Buranawuti¹, Michael P Boyle², Suzanne Cheng³, Lori L Steiner³, Kathryn McDougal¹, M Daniele Fallin⁴, Christian Merlo², Pamela L Zeitlin⁵, Beryl J Rosenstein⁵, Peter J Mogayzel, Jr⁵, Xinjing Wang¹, Garry R Cutting¹

¹ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
² Departments of Medicine, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
³ Department of Human Genetics, Roche Molecular Systems Inc., Alameda, California, USA
⁴ Department of Epidemiology Johns Hopkins/Bloomberg School of Public Health, Baltimore, Maryland, USA
⁵ Departments of Pediatrics, Johns Hopkins University School of Medicine Baltimore, Maryland, USA

Correspondence to:
Dr G R Cutting
BRB 559, 733 N. Broadway, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA; gcutting{at}jhmi.edu

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 (TNF), transforming growth factor ß1 (TGFß1) or mannose-binding lectin (MBL2)) differed among patients with cystic fibrosis grouped according to age and survival status.

Methods: Genotypes of four variants (TNF-238, TNF-308, TGFß1-509 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 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 TNF-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-238G/G vs G/A; p = 0.0015 and MBL2: A/A vs O/O; p = 0.009). The hazard ratio for TNF-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: TNF-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival of cystic fibrosis.

Abbreviations: MBL, mannose-binding lectin; SNP, single nucleotide polymorphism; TGF, transforming growth factor

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