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Variants in mannose-binding lectin and tumour necrosis factor α affect survival in cystic fibrosis
  1. Kitti Buranawuti1,
  2. Michael P Boyle2,
  3. Suzanne Cheng3,
  4. Lori L Steiner3,
  5. Kathryn McDougal1,
  6. M Daniele Fallin4,
  7. Christian Merlo2,
  8. Pamela L Zeitlin5,
  9. Beryl J Rosenstein5,
  10. Peter J Mogayzel, Jr5,
  11. Xinjing Wang1,
  12. Garry R Cutting1
  1. 1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  2. 2Departments of Medicine, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  3. 3Department of Human Genetics, Roche Molecular Systems Inc., Alameda, California, USA
  4. 4Department of Epidemiology Johns Hopkins/Bloomberg School of Public Health, Baltimore, Maryland, USA
  5. 5Departments of Pediatrics, Johns Hopkins University School of Medicine Baltimore, Maryland, USA
  1. Correspondence to:
 Dr G R Cutting
 BRB 559, 733 N. Broadway, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA; gcutting{at}


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 α (TNFα), transforming growth factor β1 (TGFβ1) or mannose-binding lectin (MBL2)) differed among patients with cystic fibrosis grouped according to age and survival status.

Methods: Genotypes of four variants (TNFα-238, TNFα-308, TGFβ1-509 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 TNFα-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 (TNFα-238G/G vs G/A; p =  0.0015 and MBL2: A/A vs O/O; p = 0.009). The hazard ratio for TNFα-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:TNFα-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival of cystic fibrosis.

  • MBL, mannose-binding lectin
  • SNP, single nucleotide polymorphism
  • TGF, transforming growth factor

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  • Published Online First 11 December 2006

  • Funding: This study is supported by grants from the Cystic Fibrosis Foundation (US), the NHLBI (HL68927, HL6618 and HL71847) and the NIDDK (DK44003).

  • Competing interests: Suzanne Cheng and Lori Steiner are employees of Roche Molecular Systems Inc. that provided genotyping reagents under a research collaboration. Garry R Cutting is a Consultant for Roche Molecular Systems.